Claims:

1. A compound having formula I: ##STR00530## wherein, A and A' are
independently selected from the group consisting of a single bond,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--S(O)k--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p--,
--(CR2)n--C(O)--O--(CR2)p--,
--(CR2)n--N(RN)--S(O)k--N(RN)--(CR2)p--
- and --(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of ##STR00531##
wherein: X1 is CH2, NH, O or S, Y1, Y2 and Z1
are each independently CH or N, X2 is NH, O or S, V is
--CH2--CH2--, --CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,
##STR00532## optionally includes 1 or 2 nitrogens as heteroatoms on
the phenyl residue, the carbons of the heteroaryl group are each
independently optionally substituted with a substituent selected from the
group consisting of --OH, --CN, --NO2, halogen, C1 to C12
alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, the nitrogens, if
present, of the heteroaryl group are each independently optionally
substituted with a substituent selected from the group consisting of
--OH, C1 to C12 alkyl, C1 to C12 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, a and b are independently 1, 2, or 3, c and d are
independently 1 or 2, n and p are independently 0, 1, 2 or 3, k is 0, 1,
or 2, each R is independently selected from the group consisting of
hydrogen, --OH, --CN, --NO2, halogen, C1 to C12 alkyl,
C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, each RN is
independently selected from the group consisting of hydrogen, --OH,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate and sulfonamide, and wherein
for each A and A', B may be attached to either side of A and A' so that
in the example of A or A' being ##STR00533## the A-B-A' can be any
of: ##STR00534## B is Q or Q-Q, wherein each Q is independently
selected from the group consisting of a cycloalkyl group, cycloalkenyl
group, heterocycle, aryl group or heteroaryl group, with the proviso that
only one Q is a six member aromatic ring when B is Q-Q and with the
proviso that if B is Q-Q, any Q is that is polycyclic is connected to the
remainder of the molecule through only one cycle of the polycycle;
Rc, Rd, Re and Rf are each independently selected
from the group consisting of: hydrogen, C1 to C8 alkyl, C1
to C8 heteroalkyl, aralkyl and a 4- to 8-membered ring which may be
cycloalkyl, heterocycle, heteroaryl or aryl, wherein, each hetero atom,
if present, is independently N, O or S, each of Rc, Rd, Re
and Rf may optionally be substituted by C1 to C8 alkyl,
C1 to C8 heteroalkyl, aralkyl, or a 4- to 8-membered ring which
may be cycloalkyl, heterocycle, heteroaryl or aryl and wherein each
heteroatom, if present, is independently N, O or S, Rc and Rd
are optionally joined to form a 4- to 8-membered heterocycle which is
optionally fused to another 3- to 6-membered heterocycle or heteroaryl
ring, and Re and Rf are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle or heteroaryl ring; Y and Y' are each
independently carbon or nitrogen; and Z and Z' are independently selected
from the group consisting of hydrogen, C1 to C8 alkyl, C1
to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl,
aralkyl, 1-3 amino acids,
--[U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--U--
-(CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R8,
--U--(CR.sup.4.sub.2)t--R8 and
--[U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--U--
-(CR.sup.4.sub.2)t--O--(CR.sup.4.sub.2)t--R8, wherein, U is
selected from the group consisting of --C(O)--, --C(S)-- and
--S(O)2--, each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, R8 is selected from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R.sup.81.sub.2,
--S(O)2--R81 and --S(O)2--N--R.sup.81.sub.2, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, optionally, R7 and
R8 together form a 4-7 membered ring, each t is independently 0, 1,
2, 3, or 4, and u is 0, 1, or 2.

2. The compound of claim 1 wherein each Q is independently optionally
substituted with one or more substituents each independently selected
from the group consisting of --OH, --CN, --NO2, halogen, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, and if Q is not
aromatic, it is optionally substituted with oxo.

3. The compound of claim 2 wherein each Q is independently optionally
substituted with --CN, --OCF3, --OCHF2, --CF3, or --F.

4. The compound of claim 1 wherein B is selected from the group
consisting of ##STR00535## ##STR00536## wherein: ##STR00537## is a
divalent aryl or heteroaryl group which may be polycyclic with varying
connective patterns; V is --CH2--, --CH2--CH2--,
--CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0;
each r and s is independently 0, 1, 2, 3, or 4; each Ra is
independently selected from the group consisting of --OH, --CN,
--NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; and each Rb is independently C1-C12
alkyl, hydroxyl, halogen, or oxo.

5. The compound of claim 4 wherein ##STR00538## is selected from the
group consisting of ##STR00539## wherein * indicates attachment points
to the remainder of the compound, and each phenyl residue optionally
includes 1 or 2 nitrogens as heteroatoms.

7. The compound of any one of claims 1 to 6 wherein A and A' are
independently selected from the group consisting of a single bond,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p-- and
--(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of ##STR00540##

8. The compound of claim 7 wherein A and A' are independently selected
from the group consisting of a single bond, ##STR00541## ##STR00542##

9. The compound of any of the preceding claims wherein Rc, Rd,
Re and Rf are each independently selected from the group
consisting of: hydrogen, C1 to C8 alkyl and C1 to C8
heteroalkyl, wherein, each hetero atom, if present, is independently N, O
or S, Rc and Rd are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle, and Re and Rf are optionally joined to
form a 4- to 8-membered heterocycle which is optionally fused to another
3- to 6-membered heterocycle.

10. The compound of claim 9 wherein one or both of Rc and Rd or
Re and Rf are optionally joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle.

11. The compound of claim 9 wherein Rc and Rd are joined and
form a heterocyclic fused ring system selected from the group consisting
of: ##STR00543## wherein RN is selected from the group consisting
of hydrogen, --OH, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide.

12. The compound of claim 9 or 11 wherein Re and Rf are joined
and form a heterocyclic fused ring system selected from the group
consisting of: ##STR00544## wherein RN is selected from the group
consisting of hydrogen, --OH, C1 to C12 alkyl, C1 to
C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,
sulfonate and sulfonamide.

13. The compound of claim 1 having formula III: ##STR00545## wherein A
is selected from the group consisting of ##STR00546## A' is selected
from the group consisting of single bond, ##STR00547## ##STR00548##
##STR00549## --(CR2)n--O--(CR2)p--,
--(CR2)n--C(O)N(RN)--(CR2)p-- and
--(CR2)n--N(RN)C(O)--(CR2)p-- wherein RN is
selected from the group consisting of hydrogen, --OH, C1 to C12
alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate and sulfonamide; ##STR00550##
optionally includes 1 or 2 nitrogens as heteroatoms; each Ra is
independently selected from the group consisting of --OH, --CN,
--NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; and r is selected from the group consisting of 0,
1, 2, 3, or 4. ##STR00551##

14. The compound of claim 13 wherein A' is
--(CR2)n--C(O)N(RN)--(CR2)p--, or
--(CR2)n--N(RN)C(O)--(CR2)p--.

15. The compound of claim 14 wherein A' is ##STR00552##

16. The compound of claim 15 having formula IIIa: ##STR00553## wherein
X and X' are each independently selected from the group consisting of a
bond, --CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.

17. The compound of claim 13 wherein A' is selected from the group
consisting of ##STR00554##

18. The compound of claim 17 having formula IIIb: ##STR00555## wherein
X and X' are each independently selected from the group consisting of a
bond, --CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.

19. The compound of claim 1 having formula IV: ##STR00556## wherein A
and A' are independently selected from the group consisting of single
bond, ##STR00557## ##STR00558##
--(CR2)n--O--(CR2)p-- and
--(CR2)n--C(O)N(RN)--(CR2)p--, wherein: RN
is selected from the group consisting of hydrogen, --OH, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate and sulfonamide; ##STR00559##
optionally includes 1, 2, 3, or 4 nitrogens as heteroatoms; each Ra
is independently selected from the group consisting of --OH, --CN,
--NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; r is 0, 1, 2, 3 or 4; each Rb is
independently C105 alkyl, hydroxyl, halogen, or oxo; s is 0, 1, 2,
3, 4, 5, or 6; and each of X1 and X2 are independently C or N.

20. The compound of claim 19 having formula IVa: ##STR00560##

21. The compound of claim 20 having formula IVb: ##STR00561## wherein X
and X' are each independently selected from the group consisting of a
bond, --CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.

22. The compound of claim 1 having formula V: ##STR00562## wherein A
and A' are independently selected from the group consisting of single
bond ##STR00563## ##STR00564##
--(CR2)n--O--(CR2)p-- and
--(CR2)n--C(O)--N(RN)--(CR2)p--, wherein RN
is selected from the group consisting of hydrogen, --OH, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate and sulfonamide; X3 is chosen from
the group consisting of --CH2--, --CH2--CH2--,
--CH═CH--, --O--, --S--, --S(O)1-2--, --CH2--O--,
--NR1-- and --CH2--NR1-- wherein R1 is chosen from
the group consisting of hydrogen, C1 to C8 alkyl, and C1
to C8 heteroalkyl; ##STR00565## optionally includes 1 or 2
nitrogens as heteroatoms; each Ra is independently selected from the
group consisting of --OH, --CN, --NO2, halogen, C1 to C12
alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino; and r is 0, 1, 2,
3 or 4.

23. The compound of claim 22 having formula Va: ##STR00566##

24. The compound of claim 23 having formula Vb: ##STR00567## wherein X
and X' are each independently selected from the group consisting of a
bond, --CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.

25. A compound having formula VI: ##STR00568## wherein each
##STR00569## is independently a divalent aryl or heteroaryl group which
may be polycyclic with varying connective patterns; each r is
independently 0, 1, 2, 3, or 4; each Ra is independently selected
from the group consisting of --OH, --CN, --NO2, halogen, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino; A and A' are
independently selected from the group consisting of a single bond,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--S(O)k--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p--,
--(CR2)n--C(O)--O--(CR2)p--,
--(CR2)n--N(RN)--S(O)k--N(RN)--(CR2)p--
- and --(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of ##STR00570##
wherein: X1 is CH2, NH, O or S, Y1, Y2 and Z1
are each independently CH or N, X2 is NH, O or S, V is
--CH2--CH2--, --CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,
##STR00571## optionally includes 1 or 2 nitrogens as heteroatoms on
the phenyl residue, the carbons of the heteroaryl group are each
independently optionally substituted with a substituent selected from the
group consisting of --OH, --CN, --NO2, halogen, C1 to C12
alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, the nitrogens, if
present, of the heteroaryl group are each independently optionally
substituted with a substituent selected from the group consisting of
--OH, C1 to C12 alkyl, C1 to C12 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, a and b are independently 1, 2, or 3, c and d are
independently 1 or 2, n and p are independently 0, 1, 2 or 3, k is 0, 1,
or 2, each R is independently selected from the group consisting of
hydrogen, --OH, --CN, --NO2, halogen, C1 to C12 alkyl,
C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, each RN is
independently selected from the group consisting of hydrogen, --OH,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate and sulfonamide, and wherein
for each A and A', B may be attached to either side of A and A' so that
in the example of A or A' being ##STR00572## the A-B-A' can be any of:
##STR00573## Rc, Rd, Re and Rf are each
independently selected from the group consisting of: hydrogen, C1 to
C8 alkyl, C1 to C8 heteroalkyl, aralkyl and a 4- to
8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or aryl,
wherein, each hetero atom, if present, is independently N, O or S, each
of Rc, Rd, Re and Rf may optionally be substituted by
C1 to C8 alkyl, C1 to C8 heteroalkyl, aralkyl, or a
4- to 8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or
aryl and wherein each heteroatom, if present, is independently N, O or S,
Rc and Rd are optionally joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle or heteroaryl ring, and Re and Rf are optionally
joined to form a 4- to 8-membered heterocycle which is optionally fused
to another 3- to 6-membered heterocycle or heteroaryl ring; Y and Y' are
each independently carbon or nitrogen; and Z and Z' are independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, 1-3 amino acids,
--[U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--U--
-(CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R8,
--U--(CR.sup.4.sub.2)t--R8 and
--[U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--U--
-(CR.sup.4.sub.2)t--O--(CR.sup.4.sub.2)t--R8, wherein, U is
selected from the group consisting of --C(O)--, --C(S)-- and
--S(O)2--, each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, R8 is selected from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R.sup.81.sub.2,
--S(O)2--R81 and --S(O)2--N--R.sup.81.sub.2, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, optionally, R7 and
R8 together form a 4-7 membered ring, each t is independently 0, 1,
2, 3, or 4, and u is 0, 1, or 2.

26. The compound of claim 25 wherein each ##STR00574## is independently
selected from the group consisting of ##STR00575## wherein * indicates
attachment points to the remainder of the compound and each phenyl
residue optionally includes 1 or 2 nitrogens as heteroatoms.

27. The compound of one of claim 25 or 26 wherein A and A' are
independently selected from the group consisting of a single bond,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p-- and
--(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of ##STR00576##

28. The compound of claim 27 wherein A and A' are independently selected
from the group consisting of a single bond, ##STR00577## ##STR00578##

29. The compound according to any one of claim 13, 14, 15, 17, 19, 20,
22, 23, 25, 26, 27 or 28 wherein Rc, Rd, Re and Rf
are each independently selected from the group consisting of: hydrogen,
C1 to C8 alkyl and C1 to C8 heteroalkyl, wherein,
each hetero atom, if present, is independently N, O or S, Rc and
Rd are optionally joined to form a 4- to 8-membered heterocycle
which is optionally fused to another 3- to 6-membered heterocycle, and
Re and Rf are optionally joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle.

30. The compound according to claim 30 wherein one of Rc and Rd
or Re and Rf are joined to form a 4- to 8-membered heterocycle
which is optionally fused to another 3- to 6-membered heterocycle.

31. The compound according to claim 30 wherein both of Rc and
Rd and Re and Rf are joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle.

32. The compound of claim 31 wherein Rc and Rd are joined and
form a heterocyclic fused ring system selected from the group consisting
of: ##STR00579## wherein RN is selected from the group consisting
of hydrogen, --OH, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide.

33. The compound of any one of claims 29-32 wherein Re and Rf
are joined and form a heterocyclic fused ring system selected from the
group consisting of: ##STR00580## Wherein RN is selected from the
group consisting of hydrogen, --OH, C1 to C12 alkyl, C1 to
C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,
sulfonate and sulfonamide.

34. The compound according to any one of claims 13-33 wherein each
Ra is independently --CN, --OCF3, --OCHF2, --CF3, or
--F.

37. The compound according to claim 19 or 22 wherein A and A' are each
independently ##STR00581## or
--(CR2)n--C(O)N(RN)--(CR2)p--.

38. The compound according to any one of claims 1-37 wherein Z and Z' are
each 1-3 amino acids.

39. The compound according to claim 38 wherein the amino acids are in the
D configuration.

40. The compound of any one of claims 1-37 wherein Z and Z' are each
independently selected from the group consisting of
--[U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--U--
-(CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R8,
--U--(CR.sup.4.sub.2)t--R8 and
--[U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--U--
-(CR.sup.4.sub.2)t--O--(CR.sup.4.sub.2)t--R.sup.8.

41. The compound of claim 40 wherein one or both of Z and Z' are
--[U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--U--
-(CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R.sup.8.

42. The compound of claim 41 wherein one or both of Z and Z' are
--U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t--U--(CR.sup-
.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R.sup.8.

43. The compound of claim 41 wherein one or both of Z and Z' are
--U--(CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R.sup.8.

44. The compound of claim 41 wherein either one or both of Z and Z' are
--[C(O)--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--
-U--(CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R.sup.8.

45. The compound of claim 44 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t--U--(CR.-
sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R.sup.8.

46. The compound of claim 44 wherein one or both of Z and Z' are
--[C(O)--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--
-C(O)--(CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R.sup.8.

47. The compound of claim 46 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t--C(O)--(-
CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R.sup.8.

48. The compound of claim 44 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)t--NR7--(CR.sup.4.sub.2)t--R8-
.

49. The compound of claim 48 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)n--NR7--(CR.sup.4.sub.2)n--C(O)--R-
.sup.81.

50. The compound of claim 49 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)n--NR7--C(O)--R.sup.81.

51. The compound of claim 48 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)n--NR7--(CR.sup.4.sub.2)n--C(O)--O-
--R.sup.81.

52. The compound of claim 51 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)n--NR7--C(O)--O--R.sup.81.

53. The compound of claim 40 wherein one or both of Z and Z' are
--U--(CR.sup.4.sub.2)t--R.sup.8.

54. The compound of claim 53 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)t--R.sup.8.

55. The compound of claim 40 wherein one or both of Z and Z' are
--[U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t]u--U--
-(CR.sup.4.sub.2)t--O--(CR.sup.4.sub.2)t--R.sup.8.

56. The compound of claim 55 wherein one or both of Z and Z' are
--U--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t--U--(CR.sup-
.4.sub.2)t--O--(CR.sup.4.sub.2)t--R.sup.8.

57. The compound of claim 64 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)t--NR5--(CR.sup.4.sub.2)t--C(O)--(-
CR.sup.4.sub.2)t--O--(CR.sup.4.sub.2)t--R.sup.8.

58. The compound of claim 55 wherein one or both of Z and Z' are
--U--(CR.sup.4.sub.2)t--O--(CR.sup.4.sub.2)t--R.sup.8.

59. The compound of claim 58 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)t--O--(CR.sup.4.sub.2)t--R.sup.8.

60. The compound of claim 40 wherein one or both of Z and Z' are
--C(O)--(CR.sup.4.sub.2)n--NR7--R8 wherein R7 and
R8 together form a 4-7 membered ring.

61. A pharmaceutical composition comprising any one of the compounds of
claims 1-60.

62. The use of the compound of any one of claims 1-60 in the manufacture
of a medicament.

63. The use of a compound of claim 62 wherein the medicament is for the
treatment of hepatitis C.

64. A method of treating hepatitis C comprising administering to a
subject in need thereof, a therapeutically effective amount of any one of
the compounds of claims 1-61.

[0003] HCV is a single-stranded RNA virus that is a member of the
Flaviviridae family. The virus shows extensive genetic heterogeneity as
there are currently seven identified genotypes and more than 50
identified subtypes. In HCV infected cells, viral RNA is translated into
a polyprotein that is cleaved into ten individual proteins. At the amino
terminus are structural proteins: the core (C) protein and the envelope
glycoproteins, E1 and E2. p7, an integral membrane protein, follows E1
and E2. Additionally, there are six non-structural proteins, NS2, NS3,
NS4A, NS4B, NS5A and NS5B, which play a functional role in the HCV
lifecycle. (see, for example, Lindenbach, B. D. and C. M. Rice, Nature.
436:933-938, 2005).

[0004] Infection by HCV is a serious health issue. It is estimated that
170 million people worldwide are chronically infected with HCV. HCV
infection can lead to chronic hepatitis, cirrhosis, liver failure and
hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide
cause of liver-related premature mortality.

[0005] The present standard of care treatment regimen for HCV infection
involves interferon-alpha, alone, or in combination with ribavirin. The
treatment is cumbersome and sometimes has debilitating and severe side
effects and many patients do not durably respond to treatment. New and
effective methods of treating HCV infection are urgently needed.

SUMMARY OF THE INVENTION

[0006] Essential features of the NS5A protein of HCV make it an ideal
target for inhibitors. The present disclosure describes a class of
compounds targeting the NS5A protein and methods of their use to treat
HCV infection in humans.

[0007] In a first aspect, compounds of formula I are provided:

##STR00001##

wherein, [0008] A and A' are independently selected from the group
consisting of a single bond,
--(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--S(O)k--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p--,
--(CR2)n--C(O)--O--(CR2)p--,
--(CR2)n--N(RN)--S(O)k--N(RN)--(CR2)p--
- and --(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of

[0008] ##STR00002## wherein: [0009] X1 is CH2, NH, O or
S, [0010] Y1, Y2 and Z1 are each independently CH or N,
[0011] X2 is NH, O or S, [0012] V is --CH2--CH2--,
--CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,

[0012] ##STR00003## optionally includes 1 or 2 nitrogens as
heteroatoms on the phenyl residue, [0013] the carbons of the heteroaryl
group are each independently optionally substituted with a substituent
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, [0014]
the nitrogens, if present, of the heteroaryl group are each independently
optionally substituted with a substituent selected from the group
consisting of --OH, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, [0015] a and b are independently 1, 2, or 3. [0016] c and d
are independently 1 or 2, [0017] n and p are independently 0, 1, 2 or 3,
[0018] k is 0, 1, or 2, [0019] each R is independently selected from the
group consisting of hydrogen, --OH, --CN, --NO2, halogen, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, [0020] each
RN is independently selected from the group consisting of hydrogen,
--OH, C1 to C12 alkyl, C1 to C12 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, and [0021] wherein for each A and A', B may be attached to
either side of A and A' so that in the example of A or A' being

[0021] ##STR00004## the A-B-A' can be any of:

##STR00005## [0022] B is Q or Q-Q, wherein each Q is independently
selected from the group consisting of a cycloalkyl group, cycloalkenyl
group, heterocycle, aryl group or heteroaryl group, with the proviso that
only one Q is a six member aromatic ring when B is Q-Q and with the
proviso that if B is Q-Q, any Q is that is polycyclic is connected to the
remainder of the molecule through only one cycle of the polycycle; [0023]
Rc, Rd, Re and Rf are each independently selected
from the group consisting of: hydrogen, C1 to C8 alkyl, C1
to C8 heteroalkyl, aralkyl and a 4- to 8-membered ring which may be
cycloalkyl, heterocycle, heteroaryl or aryl, wherein, [0024] each hetero
atom, if present, is independently N, O or S, [0025] each of Rc,
Rd, Re and Rf may optionally be substituted by C1 to
C8 alkyl, C1 to C8 heteroalkyl, aralkyl, or a 4- to
8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or aryl
and wherein each heteroatom, if present, is independently N, O or S,
[0026] Rc and Rd are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle or heteroaryl ring, and [0027] Re and Rf
are optionally joined to form a 4- to 8-membered heterocycle which is
optionally fused to another 3- to 6-membered heterocycle or heteroaryl
ring; [0028] Y and Y' are each independently carbon or nitrogen; and
[0029] Z and Z' are independently selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8 and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t--R8, wherein,
[0030] U is selected from the group consisting of --C(O)--, --C(S)-- and
--S(O)2--, [0031] each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, [0032] R8 is selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81 and --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, [0033] optionally, R7 and
R8 together form a 4-7 membered ring, [0034] each t is independently
0, 1, 2, 3, or 4, and [0035] u is 0, 1, or 2.

[0036] In a first embodiment of the first aspect, each Q is independently
optionally substituted with one or more substituents each independently
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, and if
Q is not aromatic, it is optionally substituted with oxo.

[0037] In a second embodiment of the first aspect, each Q is independently
optionally substituted with --CN, --OCF3, --OCHF2, --CF3
or --F.

[0038] In a third embodiment of the first aspect, B is selected from the
group consisting of

##STR00006## ##STR00007##

wherein:

##STR00008##

is a divalent aryl or heteroaryl group which may be polycyclic with
varying connective patterns; [0039] V is --CH2--,
--CH2--CH2--, --CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0;
[0040] each r and s is independently 0, 1, 2, 3, or 4; [0041] each
Ra is independently selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; and [0042] each Rb is independently
C1-C12 alkyl, hydroxyl, halogen, or oxo.

[0043] In a fourth embodiment of the first aspect,

##STR00009##

if present, is selected from the group consisting of

##STR00010##

wherein * indicates attachment points to the remainder of the compound,
and each phenyl residue optionally includes 1 or 2 nitrogens as
heteroatoms.

[0044] In a fifth embodiment of the first aspect, each Ra, if
present, --CN, --OCF3, --OCHF2, --CF3, or --F.

[0045] In a sixth embodiment of the first aspect, A and A' are
independently selected from the group consisting of a single bond,
--(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p-- and
--(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting oF

##STR00011##

[0046] In a seventh embodiment of the first aspect, A and A' are
independently selected from the group consisting of a single bond,

##STR00012## ##STR00013##

[0047] In an eighth embodiment of the first aspect, Rc, Rd,
Re and Rf are each independently selected from the group
consisting of: hydrogen, C1 to C8 alkyl and C1 to C8
heteroalkyl, wherein, [0048] each hetero atom, if present, is
independently N, O or S, [0049] Rc and Rd are optionally joined
to form a 4- to 8-membered heterocycle which is optionally fused to
another 3- to 6-membered heterocycle, and [0050] Re and Rf are
optionally joined to form a 4- to 8-membered heterocycle which is
optionally fused to another 3- to 6-membered heterocycle.

[0051] In a ninth embodiment of the first aspect, one or both of Rc
and Rd or Re and Rf are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle.

[0052] In a tenth embodiment of the first aspect, Rc and Rd are
joined and form a heterocyclic fused ring system selected from the group
consisting of:

[0082] In a first embodiment of the fourth aspect, A and A' are each
independently

##STR00040##

or --(CR2)n--C(O)N(RN)--(CR2)p--.

[0083] In a second embodiment of the fourth aspect, compounds have formula
Va:

##STR00041##

[0084] In a third embodiment of the fourth aspect, compounds have formula
Vb:

##STR00042##

wherein X and X' are each independently selected from the group
consisting of a bond, --CH2, --CH2--CH2--, --CH═CH--,
--O--, --S--, --S(O)1-2--, --CH2O--, --CH2S--,
--CH2S(O)1-2-- and --CH2N(R1)--, wherein R1 is
chosen from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted
sulfonyl.

[0085] In a fifth aspect of the invention, compounds have formula VI:

##STR00043##

wherein [0086] each

##STR00044##

[0086] is independently a divalent aryl or heteroaryl group which may be
polycyclic with varying connective patterns; [0087] each r is
independently 0, 1, 2, 3, or 4; [0088] each Ra is independently
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; [0089]
A and A' are independently selected from the group consisting of a single
bond, --(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--S(O)k--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p--,
--(CR2)n--C(O)--O--(CR2)p--,
--(CR2)n--N(RN)--S(O)k--N(RN)--(CR2)p--
- and --(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of

[0089] ##STR00045## wherein: [0090] X1 is CH2, NH, O or
S, [0091] Y1, Y2 and Z1 are each independently CH or N,
X2 is NH, O or S, [0092] V is --CH2--CH2--, --CH═CH--,
--N═CH--, (CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,

[0092] ##STR00046## optionally includes 1 or 2 nitrogens as
heteroatoms on the phenyl residue, [0093] the carbons of the heteroaryl
group are each independently optionally substituted with a substituent
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, [0094]
the nitrogens, if present, of the heteroaryl group are each independently
optionally substituted with a substituent selected from the group
consisting of --OH, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, [0095] a and b are independently 1, 2, or 3. [0096] c and d
are independently 1 or 2, [0097] n and p are independently 0, 1, 2 or 3,
[0098] k is 0, 1, or 2, [0099] each R is independently selected from the
group consisting of hydrogen, --OH, --CN, --NO2, halogen, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, [0100] each
RN is independently selected from the group consisting of hydrogen,
--OH, C1 to C12 alkyl, C1 to C12 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, and [0101] wherein for each A and A', B may be attached to
either side of A and A' so that in the example of A or A' being

[0101] ##STR00047## the A-B-A' can be any of:

##STR00048## [0102] Rc, Rd, Re and Rf are each
independently selected from the group consisting of: hydrogen, C1 to
C8 alkyl, C1 to C8 heteroalkyl, aralkyl and a 4- to
8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or aryl,
wherein, [0103] each hetero atom, if present, is independently N, O or
S, [0104] each of Rc, Rd, Re and Rf may optionally be
substituted by C1 to C8 alkyl, C1 to C8 heteroalkyl,
aralkyl, or a 4- to 8-membered ring which may be cycloalkyl, heterocycle,
heteroaryl or aryl and wherein each heteroatom, if present, is
independently N, O or S, [0105] Rc and Rd are optionally joined
to form a 4- to 8-membered heterocycle which is optionally fused to
another 3- to 6-membered heterocycle or heteroaryl ring, and [0106]
Re and Rf are optionally joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle or heteroaryl ring; [0107] Y and Y' are each independently
carbon or nitrogen; and [0108] Z and Z' are independently selected from
the group consisting of hydrogen, C1 to C8 alkyl, C1 to
C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
1-3 amino acids,
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8 and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t)--R8, wherein,
[0109] U is selected from the group consisting of --C(O)--, --C(S)-- and
--S(O)2--, [0110] each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, [0111] R8 is selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81 and --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, [0112] optionally, R7 and
R8 together form a 4-7 membered ring, [0113] each t is independently
0, 1, 2, 3, or 4, and [0114] u is 0, 1, or 2.

[0115] In a first embodiment of the fifth aspect, each

##STR00049##

is independently selected from the group consisting of

##STR00050##

wherein * indicates attachment points to the remainder of the compound,
and each phenyl residue optionally includes 1 or 2 nitrogens as
heteroatoms.

[0116] In a second embodiment of the fifth aspect, A and A' are
independently selected from the group consisting of a single bond,
--(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p-- and
--(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of

##STR00051##

[0117] In a third embodiment of the fifth aspect, A and A' are
independently selected from the group consisting of a single bond

##STR00052## ##STR00053##

[0118] In a fourth embodiment of the fifth aspect, A and A' are each
independently

##STR00054##

or --(CR2)n--C(O)N(RN)--(CR2)p--.

[0119] In a sixth aspect of the invention, in any compound of the second
through fifth aspects, Rc, Rd, Re and Rf are each
independently selected from the group consisting of: hydrogen, C1 to
C8 alkyl and C1 to C8 heteroalkyl, wherein, [0120] each
hetero atom, if present, is independently N, O or S, [0121] Rc and
Rd are optionally joined to form a 4- to 8-membered heterocycle
which is optionally fused to another 3- to 6-membered heterocycle, and
[0122] Re and Rf are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle.

[0123] In a first embodiment of the sixth aspect, one of Rc and
Rd or Re and Rf are joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle.

[0124] In a second embodiment of the sixth aspect, both of Rc and
Rd and Re and Rf are joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle.

[0125] In a third embodiment of the sixth aspect, Rc and Rd are
joined and form a heterocyclic fused ring system selected from the group
consisting of:

[0127] In a seventh aspect of the invention, each Ra, if present in a
compound of any of the second through sixth aspects, is independently
--CN, --OCF3, --OCHF2, --CF3, or --F.

[0128] In an eighth aspect of the invention, if present in any compound of
any of the previous aspects, one of Y and Y' is N.

[0129] In a first embodiment of the eighth aspect, both Y and Y' are N.

[0130] In a ninth aspect of the invention, Z and Z' in any of the previous
aspects are each 1-3 amino acids.

[0131] In a first embodiment of the ninth aspect, the amino acids are in
the D configuration.

[0132] In a tenth aspect of the invention, Z and Z' in any of the previous
aspects are each independently selected from the group consisting of
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8 and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t--R8.

[0133] In a first embodiment of the tenth aspect, one or both of Z and Z'
are --[U--(CR42)t--NR5--(CR42)t]u-
--U--(CR42)t--NR7--(CR42)t--R8.

[0134] In a second embodiment of the tenth aspect, one or both of Z and Z'
are --U--(CR42)t--NR5--(CR42)t--U--(CR-
42)t--NR7--(CR42)t--R8.

[0135] In a third embodiment of the tenth aspect, one or both of Z and Z'
are --U--(CR42)t--NR7--(CR42)t--R8.

[0136] In a fourth embodiment of the tenth aspect, one or both of Z and Z'
are --[C(O)--(CR42)t--NR5--(CR42)t].su-
b.u--U--(CR42)t--NR7--(CR42)t--R8.

[0137] In a fifth embodiment of the tenth aspect, one or both of Z and Z'
are --C(O)--(CR42)t--NR5--(CR42)t--U---
(CR42)t--NR7--(CR42)t--R8.

[0138] In a sixth embodiment of the tenth aspect, one or both of Z and Z'
are --[C(O)--(CR42)t--NR5--(CR42)t].su-
b.u--C(O)--(CR42)t--NR7--(CR42)t--R.sup-
.8.

[0139] In a seventh embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)t--NR5--(CR42)t---
C(O)--(CR42)t--NR7--(CR42)t--R8.

[0140] In an eighth embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)t--NR7--(CR42)t---
R8.

[0141] In a ninth embodiment of the tenth aspect, one or both of Z and Z'
are --C(O)--(CR42)n--NR7--(CR42)n--C(O-
)--R81.

[0142] In a tenth embodiment of the tenth aspect, one or both of Z and Z'
are --C(O)--(CR42)n--NR7--C(O)--R81.

[0143] In an eleventh embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)n--NR7--(CR42)n---
C(O)--O--R81.

[0144] In a twelfth embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)n--NR7--C(O)--O--R81.

[0145] In a thirteenth embodiment of the tenth aspect, one or both of Z
and Z' are --U--(CR42)t--R8.

[0146] In a fourteenth embodiment of the tenth aspect, one or both of Z
and Z' are --C(O)--(CR42)t--R8.

[0147] In a fifteenth embodiment of the tenth aspect, one or both of Z and
Z' are --[U--(CR42)t--NR5--(CR42)t].su-
b.u--U--(CR42)t--O--(CR42)t--R8.

[0148] In a sixteenth embodiment of the tenth aspect, one or both of Z and
Z' are --U--(CR42)t--NR5--(CR42)t--U---
(CR42)t--O--(CR42)t--R8.

[0149] In a seventeenth embodiment of the tenth aspect, one or both of Z
and Z' are
--C(O)--(CR42)t--NR5--(CR42)t--C(O)--(-
CR42)t--O--(CR42)t--R8.

[0150] In an eighteenth embodiment of the tenth aspect, one or both of Z
and Z' are
--U--(CR42)t--O--(CR42)t--R8.

[0151] In a nineteenth embodiment of the tenth aspect, one or both of Z
and Z' are
--C(O)--(CR42)t--O--(CR42)t--R8.

[0152] In a twentieth embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)n--NR7--R8 wherein R7
and R8 together form a 4-7 membered ring.

[0153] In an eleventh aspect of the invention, compounds have formula VII:

##STR00057##

wherein,

##STR00058##

may include 1 or 2 nitrogens as heteroatoms, [0154] r is from 0 to 4,
[0155] each Ra is independently selected from the group consisting
of --OH, --CN, --NO2, halogen, C1 to C12 alkyl, C1 to
C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,
sulfonate, sulfonamide and amino; [0156] A and A' are independently
selected from the group consisting of

[0156] ##STR00059## --(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p-- and
--(CR2)n--C(O)N(RN)--(CR2)p--, wherein, [0157]
if A or A' is a heteroaryl group, it is optionally substituted with one
or more of the substituents selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino, and [0158] n and p are independently 0, 1, or 2,
[0159] each R is independently selected from the group consisting of
hydrogen, --OH, --CN, --NO2, halogen, C1 to C12 alkyl,
C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, [0160] RN is
selected from the group consisting of hydrogen, --OH, C1 to C12
alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate and sulfonamide, and [0161] for each A
and A',

[0161] ##STR00060## may be attached to either side of A and A' so
that in the example of A or A' being

##STR00061## the

##STR00062## can be any of:

##STR00063## [0162] B' is

[0162] ##STR00064## wherein, [0163] B' is optionally substituted
with between 1 and 4 substituents, each independently selected from the
group consisting of --OH, --CN, --NO2, halogen, C1 to C12
alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide, amino and oxo, [0164]
Xa is chosen from the group consisting of --CH2--,
--CH2--CH2--, --CH═CH--, --O--, --S--, --S(═O)2--,
--CH2--O--, --NR1-- and --CH2--NR1-- wherein R1
is chosen from the group consisting of hydrogen, C1 to C8
alkyl, and C1 to C8 heteroalkyl, and [0165] Xb is either C
or N; [0166] X and X' are each either present or absent and if present,
independently selected from the group consisting of a bond, --CH2--,
--CH2--CH2--, --CH═CH--, --O--, --S--, --S(O)2--,
--CH2O--, --CH2S--, --CH2S(O)2-- and
--CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl [0167]
Y and Y' are each independently carbon or nitrogen; and [0168] Z and Z'
are independently selected from the group consisting of hydrogen, C1
to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8 and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t--R8, wherein,
[0169] U is selected from the group consisting of --C(O)--, --C(S)-- and
--S(O)2--, [0170] each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, [0171] R8 is selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81 and --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, [0172] optionally, R7 and
R8 together form a 4-7 membered ring, [0173] each t is independently
0, 1, 2, 3, or 4, and [0174] u is 0, 1, or 2.

[0175] In a twelfth aspect of the invention, compounds have formula VIII:

##STR00065##

wherein: [0176] B' is selected from the group consisting of

##STR00066##

##STR00067##

[0176] optionally includes 1 or 2 nitrogens as heteroatoms; [0177] each
Ra is independently selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; [0178] r is 0, 1, 2, 3 or 4; [0179] X and X' are
each independently selected from the group consisting of a bond,
--CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl; [0180] each
R8 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81, --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl; and [0181] each R4 is
independently selected from the group consisting of hydrogen, C1 to
C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl and aralkyl.

[0182] In a thirteenth aspect of the invention, compounds have formula IX:

[0189] In a fourteenth aspect of the invention, compounds have formula X:

##STR00071##

wherein: [0190] B' is selected from the group consisting of

##STR00072##

##STR00073##

[0190] optionally includes 1 or 2 nitrogens as heteroatoms; [0191] each
Ra is independently selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; [0192] r is 0, 1, 2, 3 or 4; [0193] X and X' are
each independently selected from the group consisting of a bond,
--CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl; [0194] each
R8 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81, --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl; and [0195] each R4 is
independently selected from the group consisting of hydrogen, C1 to
C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl and aralkyl.

[0196] In a fifteenth aspect of the invention, compounds have formula XI:

##STR00074##

wherein: [0197] each Ra is independently selected from the group
consisting of --OH, --CN, --NO2, halogen, C1 to C12 alkyl,
C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino; [0198] r is 0, 1,
2, 3 or 4; [0199] Xa is chosen from the group consisting of
--CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(═O)2--, --CH2--O--, --NR1-- and
--CH2--NR1-- wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, and C1 to C8
heteroalkyl, [0200] each R8 is independently chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl,
--C(O)--R81, --C(S)--R81, --C(O)--O--R81,
--C(O)--N--R812, --S(O)2--R81,
--S(O)2--N--R812, wherein each R81 is independently
chosen from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl; and [0201] each R4 is independently selected from the
group consisting of hydrogen, C1 to C8 alkyl, C1 to
C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and
aralkyl.

[0202] The sixteenth aspect of the invention provides a pharmaceutical
composition comprising the compounds of the invention.

[0203] The seventeenth aspect of the invention provides the use of the
compounds of the invention in the manufacture of a medicament.

[0204] In a first embodiment of the seventeenth aspect, the medicament is
for the treatment of hepatitis C.

[0205] The eighteenth aspect of the invention provides a method of
treating hepatitis C comprising administering to a subject in need
thereof, a therapeutically effective amount of a compound of the
invention.

DETAILED DESCRIPTION

[0206] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the definitions
given below. It must be noted that, as used in the specification and the
appended claims, the singular forms "a," "an" and "the" include plural
referents unless the context clearly dictates otherwise. Definition of
standard chemistry terms may be found in reference works, including Carey
and Sundberg (2007) "Advanced Organic Chemistry 5th Ed." Vols. A and
B, Springer Science+Business Media LLC, New York. The practice of the
present invention will employ, unless otherwise indicated, conventional
methods of synthetic organic chemistry, mass spectroscopy, preparative
and analytical methods of chromatography, protein chemistry,
biochemistry, recombinant DNA techniques and pharmacology.

[0207] The term "alkanoyl" as used herein contemplates a carbonyl group
with a lower alkyl group as a substituent.

[0208] The term "alkenyl" as used herein contemplates substituted or
unsubstituted, straight and branched chain alkene radicals, including
both the E- and Z-forms, containing from two to eight carbon atoms. The
alkenyl group may be optionally substituted with one or more substituents
selected from the group consisting of halogen, --CN, --NO2,
CO2R, C(O)R, --O--R, --N(RN)2, --N(RN)C(O)R,
--N(RN)S(O)2R, --SR, --C(O)N(RN)2, --OC(O)R,
--OC(O)N(RN)2, S(O)R, SO2R, --SO3R,
--S(O)2N(RN)2, phosphate, phosphonate, cycloalkyl,
cycloalkenyl, aryl and heteroaryl.

[0209] The term "alkoxy" as used herein contemplates an oxygen with a
lower alkyl group as a substituent and includes methoxy, ethoxy, butoxy,
trifluoromethoxy and the like. It also includes divalent substituents
linked to two separated oxygen atoms such as, without limitation,
--O--(CH2)1-4--O--, --O--CF2--O--,
--O--(CH2)1-4--O--(CH2CH2--O)1-4-- and
--(O--CH2CH2--O)1-4--.

[0210] The term "alkoxycarbonyl" as used herein contemplates a carbonyl
group with an alkoxy group as a substituent.

[0211] The term "alkyl" as used herein contemplates substituted or
unsubstituted, straight and branched chain alkyl radicals containing from
one to fifteen carbon atoms. The term "lower alkyl" as used herein
contemplates both straight and branched chain alkyl radicals containing
from one to six carbon atoms and includes methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl and the like. The alkyl group may
be optionally substituted with one or more substituents selected from
halogen, --CN, --NO2, --C(O)2R, --C(O)R, --O--R,
--N(RN)2, --N(RN)C(O)R, --N(RN)S(O)2R, --SR,
--C(O)N(RN)2, --OC(O)R, --OC(O)N(RN)2, --SOR,
--SO2R, --SO3R, --S(O)2N(RN)2, phosphate,
phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

[0212] The term "alkylene," "alkenylene" and "alkynylene" as used herein
refers to the groups "alkyl," "alkenyl" and "alkynyl" respectively, when
they are divalent, ie, attached to two atoms.

[0213] The term "alkylsulfonyl" as used herein contemplates a sulfonyl
group which has a lower alkyl group as a substituent.

[0214] The term "alkynyl" as used herein contemplates substituted or
unsubstituted, straight and branched carbon chain containing from two to
eight carbon atoms and having at least one carbon-carbon triple bond. The
term alkynyl includes, for example ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 3-methyl-1-butynyl and the like. The alkynyl group may be
optionally substituted with one or more substituents selected from halo,
--CN, NO2, CO2R, C(O)R, --O--R,
--N(RN)25--N(RN)C(O)R, --N(RN)S(O)2R, --SR,
--C(O)N(RN)2, --OC(O)R, --OC(O)N(RN)2, --SOR,
--SO2R, --SO3R, --S(O)2N(RN)2, phosphate,
phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

[0215] The term "amino" as used herein contemplates a group of the
structure --NRN2.

[0216] The term "amino acid" as used herein contemplates a group of the
structure

##STR00075##

in either the D or the L configuration and includes but is not limited to
the twenty "standard" amino acids: isoleucine, leucine, lysine,
methionine, phenylalanine, threonine, tryptophan, valine, alanine,
asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,
serine, tyrosine, arginine and histidine. The present invention also
includes, without limitation, D-configuration amino acids, beta-amino
acids, amino acids having side chains as well as all non-natural amino
acids known to one skilled in the art.

[0217] The term "aralkyl" as used herein contemplates a lower alkyl group
which has as a substituent an aromatic group, which aromatic group may be
substituted or unsubstituted. The aralkyl group may be optionally
substituted with one or more substituents selected from halogen, --CN,
--NO2, --CO2R, --C(O)R, --O--R, --N(RN)2,
--N(RN)C(O)R, --N(RN)S(O)2R, --SR, --C(O)N(RN)2,
--OC(O)R, --OC(O)N(RN)2, --SOR, --SO2R, --SO3R,
--S(O)2N(RN)2, phosphate, phosphonate, cycloalkyl,
cycloalkenyl, aryl and heteroaryl.

[0218] The terms "aryl," "aromatic group" or "aromatic ring" as used
herein contemplates substituted or unsubstituted single-ring and multiple
aromatic groups (for example, phenyl, pyridyl and pyrazole, etc.) and
polycyclic ring systems (naphthyl and quinolinyl, etc.). The polycyclic
rings may have two or more rings in which two atoms are common to two
adjoining rings (the rings are "fused") wherein at least one of the rings
is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls,
aryl, heterocycles and/or heteroaryls. The aryl group may be optionally
substituted with one or more substituents selected from halogen, alkyl,
--CN, --NO2, --CO2R, --C(O)R, --O--R, --N(RN)2,
--N(RN)C(O)R, --N(RN)S(O)2R, --SR, --C(O)N(RN)2,
--OC(O)R, --OC(O)N(RN)2, --SOR, --SO2R, --SO3R,
--S(O)2N(RN)2, --SiR3, --P(O)R, phosphate,
phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

[0219] The term "arylsulfonyl" as used herein contemplates a sulfonyl
group which has as a substituent an aryl group. The term is meant to
include, without limitation, monovalent as well as multiply valent aryls
(eg, divalent aryls).

[0220] The term "carbamoyl" as used herein contemplates a group of the
structure

##STR00076##

[0221] The term "carbonyl" as used herein contemplates a group of the
structure

##STR00077##

[0222] The term "carboxyl" as used herein contemplates a group of the
structure

##STR00078##

[0223] The term "cycloalkyl" as used herein contemplates substituted or
unsubstituted cyclic alkyl radicals containing from three to twelve
carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl and the
like. The term "cycloalkyl" also includes polycyclic systems having two
rings in which two or more atoms are common to two adjoining rings (the
rings are "fused"). The cycloalkyl group may be optionally substituted
with one or more substituents selected from halo, --CN, --NO2,
--CO2R, --C(O)R, --O--R, --N(RN)2, --N(RN)C(O)R,
--N(RN)S(O)2R, --SR, --C(O)N(RN)2, --OC(O)R,
--OC(O)N(RN)2, --SOR, --SO2R,
--S(O)2N(RN)2, phosphate, phosphonate, alkyl,
cycloalkenyl, aryl and heteroaryl.

[0224] The term "cycloalkenyl" as used herein contemplates substituted or
unsubstituted cyclic alkenyl radicals containing from four to twelve
carbon atoms in which there is at least one double bond between two of
the ring carbons and includes cyclopentenyl, cyclohexenyl and the like.
The term "cycloalkenyl" also includes polycyclic systems having two rings
in which two or more atoms are common to two adjoining rings (the rings
are "fused"). The cycloalkenyl group may be optionally substituted with
one or more substituents selected from halo, --CN, --NO2,
--CO2R, --C(O)R, --O--R, --N(RN)2, --N(RN)C(O)R,
--N(RN)S(O)2R, --SR, --C(O)N(RN)2, --OC(O)R,
--OC(O)N(RN)2, --SOR, --SO2R,
--S(O)2N(RN)2, phosphate, phosphonate, alkyl,
cycloalkenyl, aryl and heteroaryl.

[0225] The term "halo" or "halogen" as used herein includes fluorine,
chlorine, bromine and iodine.

[0226] The term "heteroalkyl" as used herein contemplates an alkyl with
one or more heteroatoms.

[0227] The term "heteroatom", particularly within a ring system, refers to
N, O and S.

[0228] The term "heterocyclic group," "heterocycle" or "heterocyclic ring"
as used herein contemplates substituted or unsubstituted aromatic and
non-aromatic cyclic radicals having at least one heteroatom as a ring
member. Preferred heterocyclic groups are those containing five or six
ring atoms which includes at least one hetero atom and includes cyclic
amines such as morpholino, piperidino, pyrrolidino and the like and
cyclic ethers, such as tetrahydrofuran, tetrahydropyran and the like.
Aromatic heterocyclic groups, also termed "heteroaryl" groups,
contemplates single-ring hetero-aromatic groups that may include from one
to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole,
oxazole, thiazole, triazole, pyrazole, oxodiazole, thiadiazole, pyridine,
pyrazine, pyridazine, pyrimidine and the like. The term heteroaryl also
includes polycyclic hetero-aromatic systems having two or more rings in
which two or more atoms are common to two adjoining rings (the rings are
"fused") wherein at least one of the rings is a heteroaryl, e.g., the
other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or
heteroaryls. Examples of polycyclic heteroaromatic systems include
quinoline, isoquinoline, cinnoline, tetrahydroisoquinoline, quinoxaline,
quinazoline, benzimidazole, benzofuran, benzothiophene, benzoxazole,
benzothiazole, indazole, purine, benzotriazole, pyrrolepyridine,
pyrrazolopyridine and the like. The heterocyclic group may be optionally
substituted with one or more substituents selected from the group
consisting of halo, alkyl, --CN, --NO2, --CO2R, --C(O)R,
--O--R, --N(RN)2, --N(RN)C(O)R, --N(RN)S(O)2R,
--SR, --C(O)N(RN)2, --OC(O)R, --OC(O)N(RN)2, --SOR,
--SO2R, --SO3R, --S(O)2N(RN)2, --SiR3,
--P(O)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and
heteroaryl.

[0229] The term "oxo" as used herein contemplates an oxygen atom attached
with a double bond.

[0230] By "pharmaceutically acceptable" or "pharmacologically acceptable"
is meant a material which is not biologically or otherwise undesirable,
i.e., the material may be administered to an individual without causing
any undesirable biological effects or interacting in a deleterious manner
with any of the components of the composition in which it is contained.

[0232] The terms "phosphate" and "phosphonate" as used herein refer to the
moieties having the following structures, respectively:

##STR00079##

[0233] The terms "salts" and "hydrates" refers to the hydrated forms of
the compound that would favorably affect the physical or pharmacokinetic
properties of the compound, such as solubility, palatability, absorption,
distribution, metabolism and excretion. Other factors, more practical in
nature, which those skilled in the art may take into account in the
selection include the cost of the raw materials, ease of crystallization,
yield, stability, solubility, hygroscopicity, flowability and
manufacturability of the resulting bulk drug.

[0234] The term sulfonamide as used herein contemplates a group having the
structure

##STR00080##

[0235] The term "sulfonate" as used herein contemplates a group having the
structure

[0240] Each RN is independently selected from the group consisting of
hydrogen, --OH, C1 to C12 alkyl, C1 to C12
heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl,
aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted
sulfonyl, sulfonate and sulfonamide. Two RN may be taken together
with C, O, N or S to which they are attached to form a five to seven
membered ring which may optionally contain a further heteroatom.

[0241] The compounds of the present invention may be used to inhibit or
reduce the activity of HCV, particularly HCV's NS5A protein. In these
contexts, inhibition and reduction of activity of the NS5A protein refers
to a lower level of the measured activity relative to a control
experiment in which the cells or the subjects are not treated with the
test compound. In particular aspects, the inhibition or reduction in the
measured activity is at least a 10% reduction or inhibition. One of skill
in the art will appreciate that reduction or inhibition of the measured
activity of at least 20%, 50%, 75%, 90% or 100%, or any number in
between, may be preferred for particular applications.

[0242] In a first aspect, compounds of formula I are provided:

##STR00084##

wherein, [0243] A and A' are independently selected from the group
consisting of a single bond,
--(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--S(O)k--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p--,
--(CR2)n--C(O)--O--(CR2)p--,
--(CR2)n--N(RN)--S(O)k--N(RN)--(CR2)p--
- and --(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of

[0243] ##STR00085## wherein: [0244] X1 is CH2, NH, O or
S, [0245] Y1, Y2 and Z1 are each independently CH or N,
[0246] X2 is NH, O or S, [0247] V is --CH2--CH2--,
--CH═CH--, --N═CH--,
--(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,

[0247] ##STR00086## optionally includes 1 or 2 nitrogens as
heteroatoms on the phenyl residue, [0248] the carbons of the heteroaryl
group are each independently optionally substituted with a substituent
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, [0249]
the nitrogens, if present, of the heteroaryl group are each independently
optionally substituted with a substituent selected from the group
consisting of --OH, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, [0250] a and b are independently 1, 2, or 3. [0251] c and d
are independently 1 or 2, [0252] n and p are independently 0, 1, 2 or 3,
[0253] k is 0, 1, or 2, [0254] each R is independently selected from the
group consisting of hydrogen, --OH, --CN, --NO2, halogen, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, [0255] each
RN is independently selected from the group consisting of hydrogen,
--OH, C1 to C12 alkyl, C1 to C12 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, and [0256] wherein for each A and A', B may be attached to
either side of A and A' so that in the example of A or A' being

[0256] ##STR00087## the A-B-A' can be any of:

##STR00088## [0257] B is Q or Q-Q, wherein each Q is independently
selected from the group consisting of a cycloalkyl group, cycloalkenyl
group, heterocycle, aryl group or heteroaryl group, with the proviso that
only one Q is a six member aromatic ring when B is Q-Q and with the
proviso that if B is Q-Q, any Q is that is polycyclic is connected to the
remainder of the molecule through only one cycle of the polycycle; [0258]
Rc, Rd, Re and Rf are each independently selected
from the group consisting of: hydrogen, C1 to C8 alkyl, C1
to C8 heteroalkyl, aralkyl and a 4- to 8-membered ring which may be
cycloalkyl, heterocycle, heteroaryl or aryl, wherein, [0259] each hetero
atom, if present, is independently N, O or S, [0260] each of Rc,
Rd, Re and Rf may optionally be substituted by C1 to
C8 alkyl, C1 to C8 heteroalkyl, aralkyl, or a 4- to
8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or aryl
and wherein each heteroatom, if present, is independently N, O or S,
[0261] Rc and Rd are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle or heteroaryl ring, and [0262] Re and Rf
are optionally joined to form a 4- to 8-membered heterocycle which is
optionally fused to another 3- to 6-membered heterocycle or heteroaryl
ring; [0263] Y and Y' are each independently carbon or nitrogen; and
[0264] Z and Z' are independently selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8 and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t--R8, wherein,
[0265] U is selected from the group consisting of --C(O)--, --C(S)-- and
--S(O)2--, [0266] each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, [0267] R8 is selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81 and --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, [0268] optionally, R7 and
R8 together form a 4-7 membered ring, [0269] each t is independently
0, 1, 2, 3, or 4, and [0270] u is 0, 1, or 2.

[0271] The compounds of the present invention include pharmaceutically
acceptable salts of I as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0272] In a first embodiment of the first aspect, each Q is independently
optionally substituted with one or more substituents each independently
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, and if
Q is not aromatic, it is optionally substituted with oxo.

[0273] In a second embodiment of the first aspect, each Q is independently
optionally substituted with --CN, --OCF3, --OCHF2, --CF3,
or --F.

[0274] In a third embodiment of the first aspect, B is selected from the
group consisting of

##STR00089## ##STR00090##

wherein:

##STR00091##

is a divalent aryl or heteroaryl group which may be polycyclic with
varying connective patterns; [0275] V is --CH2--,
--CH2--CH2--, --CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0;
[0276] each r and s is independently 0, 1, 2, 3, or 4; [0277] each
Ra is independently selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; and [0278] each Rb is independently
C1-C12 alkyl, hydroxyl, halogen or oxo.

[0279] In a fourth embodiment of the first aspect,

##STR00092##

if present, is selected from the group consisting of

##STR00093##

wherein * indicates attachment points to the remainder of the compound,
and each phenyl residue optionally includes 1 or 2 nitrogens as
heteroatoms.

[0280] In a fifth embodiment of the first aspect, each Ra, if
present, is independently --CN, --OCF3, --OCHF2, --CF3, or
--F.

[0281] In a sixth embodiment of the first aspect, A and A' are
independently selected from the group consisting of a single bond,
--(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p-- and
--(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of

##STR00094##

[0282] In a seventh embodiment of the first aspect, A and A' are
independently selected from the group consisting of a single bond,

##STR00095## ##STR00096##

[0283] In an eighth embodiment of the first aspect, Rc, Rd,
Re and Rf are each independently selected from the group
consisting of: hydrogen, C1 to C8 alkyl and C1 to C8
heteroalkyl, wherein, [0284] each hetero atom, if present, is
independently N, O or S, [0285] Rc and Rd are optionally joined
to form a 4- to 8-membered heterocycle which is optionally fused to
another 3- to 6-membered heterocycle, and [0286] Re and Rf are
optionally joined to form a 4- to 8-membered heterocycle which is
optionally fused to another 3- to 6-membered heterocycle.

[0287] In a ninth embodiment of the first aspect, one or both of Rc
and Rd or Re and Rf are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle.

[0288] In a tenth embodiment of the first aspect, Rc and Rd are
joined and form a heterocyclic fused ring system selected from the group
consisting of:

[0324] The compounds of the present invention include pharmaceutically
acceptable salts of V as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0325] In a first embodiment of the fourth aspect, A and A' are each
independently

##STR00123##

or --(CR2)n--C(O)N(RN)--(CR2)p--.

[0326] In a second embodiment of the fourth aspect, compounds have formula
Va:

##STR00124##

[0327] The compounds of the present invention include pharmaceutically
acceptable salts of Va as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0328] In a third embodiment of the fourth aspect, compounds have formula
Vb:

##STR00125##

wherein X and X' are each independently selected from the group
consisting of a bond, --CH2--, --CH2--CH2--,
--CH═CH--, --O--, --S--, --S(O)1-2--, --CH2O--,
--CH2S--, --CH2S(O)1-2-- and --CH2N(R1)--,
wherein R1 is chosen from the group consisting of hydrogen, C1
to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl,
carbamoyl and substituted sulfonyl.

[0329] The compounds of the present invention include pharmaceutically
acceptable salts of Vb as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0330] In a fifth aspect of the invention, compounds have formula VI:

##STR00126##

wherein [0331] each

##STR00127##

[0331] is independently a divalent aryl or heteroaryl group which may be
polycyclic with varying connective patterns; [0332] each r is
independently 0, 1, 2, 3, or 4; [0333] each Ra is independently
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; [0334]
A and A' are independently selected from the group consisting of a single
bond, --(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--S(O)k--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p--,
--(CR2)n--C(O)--O--(CR2)p--,
--(CR2)n--N(RN)--S(O)k--N(RN)--(CR2)p--
- and --(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of

[0334] ##STR00128## wherein: [0335] X1 is CH2, NH, O or
S, [0336] Y1, Y2 and Z1 are each independently CH or N,
[0337] X2 is NH, O or S, [0338] V is --CH2--CH2--,
--CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,

[0338] ##STR00129## optionally includes 1 or 2 nitrogens as
heteroatoms on the phenyl residue, [0339] the carbons of the heteroaryl
group are each independently optionally substituted with a substituent
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, [0340]
the nitrogens, if present, of the heteroaryl group are each independently
optionally substituted with a substituent selected from the group
consisting of --OH, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, [0341] a and b are independently 1, 2, or 3. [0342] c and d
are independently 1 or 2, [0343] n and p are independently 0, 1, 2 or 3,
[0344] k is 0, 1, or 2, [0345] each R is independently selected from the
group consisting of hydrogen, --OH, --CN, --NO2, halogen, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, [0346] each
RN is independently selected from the group consisting of hydrogen,
--OH, C1 to C12 alkyl, C1 to C12 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, and [0347] wherein for each A and A', B may be attached to
either side of A and A' so that in the example of A or A' being

[0347] ##STR00130## the A-B-A' can be any of:

##STR00131## [0348] Rc, Rd, Re and Rf are each
independently selected from the group consisting of: hydrogen, C1 to
C8 alkyl, C1 to C8 heteroalkyl, aralkyl and a 4- to
8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or aryl,
wherein, [0349] each hetero atom, if present, is independently N, O or
S, [0350] each of Rc, Rd, Re and Rf may optionally be
substituted by C1 to C8 alkyl, C1 to C8 heteroalkyl,
aralkyl, or a 4- to 8-membered ring which may be cycloalkyl, heterocycle,
heteroaryl or aryl and wherein each heteroatom, if present, is
independently N, O or S, [0351] Rc and Rd are optionally joined
to form a 4- to 8-membered heterocycle which is optionally fused to
another 3- to 6-membered heterocycle or heteroaryl ring, and [0352]
Re and Rf are optionally joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle or heteroaryl ring; [0353] Y and Y' are each independently
carbon or nitrogen; and [0354] Z and Z' are independently selected from
the group consisting of hydrogen, C1 to C8 alkyl, C1 to
C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
1-3 amino acids,
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8 and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t--R8, wherein,
[0355] U is selected from the group consisting of --C(O)--, --C(S)-- and
--S(O)2--, [0356] each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, [0357] R8 is selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81 and --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, [0358] optionally, R7 and
R8 together form a 4-7 membered ring, [0359] each t is independently
0, 1, 2, 3, or 4, and [0360] u is 0, 1, or 2.

[0361] The compounds of the present invention include pharmaceutically
acceptable salts of VI as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0362] In a first embodiment of the fifth aspect, each

##STR00132##

is independently selected from the group consisting of

##STR00133##

wherein * indicates attachment points to the remainder of the compound
and each phenyl residue optionally includes 1 or 2 nitrogens as
heteroatoms.

[0363] In a second embodiment of the fifth aspect, A and A' are
independently selected from the group consisting of a single bond,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p-- and
--(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of

##STR00134##

[0364] In a third embodiment of the fifth aspect, A and A' are
independently selected from the group consisting of a single bond,

##STR00135## ##STR00136##

[0365] In a fourth embodiment of the fifth aspect, A and A' are each
independently

##STR00137##

or --(CR2)n--C(O)N(RN)--(CR2)p--.

[0366] In a sixth aspect of the invention, in any compound of the second
through fifth aspects, Rc, Rd, Re and Rf are each
independently selected from the group consisting of: hydrogen, C1 to
C8 alkyl and C1 to C8 heteroalkyl, wherein, [0367] each
hetero atom, if present, is independently N, O or S, [0368] Rc and
Rd are optionally joined to form a 4- to 8-membered heterocycle
which is optionally fused to another 3- to 6-membered heterocycle, and
[0369] Re and Rf are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle.

[0370] In a first embodiment of the sixth aspect, one of Rc and
Rd or Re and Rf are joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle.

[0371] In a second embodiment of the sixth aspect, both of Rc and
Rd and Re and Rf are joined to form a 4- to 8-membered
heterocycle which is optionally fused to another 3- to 6-membered
heterocycle.

[0372] In a third embodiment of the sixth aspect, Rc and Rd are
joined and form a heterocyclic fused ring system selected from the group
consisting of:

[0374] In a seventh aspect of the invention, each Ra, if present in a
compound of any of the second through sixth aspects, is independently
--CN, --OCF3, --OCHF2, --CF3, or --F.

[0375] In an eighth aspect of the invention, if present in any compound of
any of the previous aspects, one of Y and Y' is N.

[0376] In a first embodiment of the eighth aspect, both Y and Y' are N.

[0377] In a ninth aspect of the invention, Z and Z' in any of the previous
aspects are each 1-3 amino acids.

[0378] In a first embodiment of the ninth aspect, the amino acids are in
the D configuration.

[0379] In a tenth aspect of the invention, Z and Z' in any of the previous
aspects are each independently selected from the group consisting of
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8 and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t--R8.

[0380] In a first embodiment of the tenth aspect, one or both of Z and Z'
are --[U--(CR42)t--NR5--(CR42)t]u-
--U--(CR42)t--NR7--(CR42)t--R8.

[0381] In a second embodiment of the tenth aspect, one or both of Z and Z'
are --U--(CR42)t--NR5--(CR42)t--U--(CR-
42)t--NR7--(CR42)t--R8.

[0382] In a third embodiment of the tenth aspect, one or both of Z and Z'
are --U--(CR42)t--NR7--(CR42)t--R8.

[0383] In a fourth embodiment of the tenth aspect, one or both of Z and Z'
are --[C(O)--(CR42)t--NR5--(CR42)t].su-
b.u--U--(CR42)t--NR7--(CR42)t--R8.

[0384] In a fifth embodiment of the tenth aspect, one or both of Z and Z'
are --C(O)--(CR42)t--NR5--(CR42)t--U---
(CR42)t--NR7--(CR42)t--R8.

[0385] In a sixth embodiment of the tenth aspect, one or both of Z and Z'
are --[C(O)--(CR42)t--NR5--(CR42)t].su-
b.u--C(O)--(CR42)t--NR7--(CR42)t--R.sup-
.8.

[0386] In a seventh embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)t--NR5--(CR42)t---
C(O)--(CR42)t--NR7--(CR42)t--R8.

[0387] In an eighth embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)t--NR7--(CR42)t---
R8.

[0388] In a ninth embodiment of the tenth aspect, one or both of Z and Z'
are --C(O)--(CR42)n--NR7--(CR42)n--C(O-
)--R81.

[0389] In a tenth embodiment of the tenth aspect, one or both of Z and Z'
are --C(O)--(CR42)n--NR7--C(O)--R81.

[0390] In an eleventh embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)n--NR7--(CR42)n---
C(O)--O--R81.

[0391] In a twelfth embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)n--NR7--C(O)--O--R81.

[0392] In a thirteenth embodiment of the tenth aspect, one or both of Z
and Z' are --U--(CR42)t--R8.

[0393] In a fourteenth embodiment of the tenth aspect, one or both of Z
and Z' are --C(O)--(CR42)t--R8.

[0394] In a fifteenth embodiment of the tenth aspect, one or both of Z and
Z' are --[U--(CR42)t--NR5--(CR42)t].su-
b.u--U--(CR42)t--O--(CR42)t--R8.

[0395] In a sixteenth embodiment of the tenth aspect, one or both of Z and
Z' are --U--(CR42)t--NR5--(CR42)t--U---
(CR42)t--O--(CR42)t--R8.

[0396] In a seventeenth embodiment of the tenth aspect, one or both of Z
and Z' are
--C(O)--(CR42)t--NR5--(CR42)t--C(O)--(-
CR42)t--O--(CR42)t--R8.

[0397] In an eighteenth embodiment of the tenth aspect, one or both of Z
and Z' are
--U--(CR42)t--O--(CR42)t--R8.

[0398] In a nineteenth embodiment of the tenth aspect, one or both of Z
and Z' are
--C(O)--(CR42)t--O--(CR42)t--R8.

[0399] In a twentieth embodiment of the tenth aspect, one or both of Z and
Z' are --C(O)--(CR42)n--NR7--R8 wherein R7
and R8 together form a 4-7 membered ring.

[0400] In an eleventh aspect of the invention, compounds have formula VII:

##STR00140##

wherein,

##STR00141##

may include 1 or 2 nitrogens as heteroatoms, [0401] r is from 0 to 4,
[0402] each Ra is independently selected from the group consisting
of --OH, --CN, --NO2, halogen, C1 to C12 alkyl, C1 to
C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl,
sulfonate, sulfonamide and amino; [0403] A and A' are independently
selected from the group consisting of

[0403] ##STR00142## --(CR2)n--O--(CR2)p-- and
--(CR2)n--C(O)N(RN)--(CR2)p--, wherein, [0404]
if A or A' is a heteroaryl group, it is optionally substituted with one
or more of the substituents selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino, and [0405] n and p are independently 0, 1, or 2,
[0406] each R is independently selected from the group consisting of
hydrogen, --OH, --CN, --NO2, halogen, C1 to C12 alkyl,
C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, [0407] RN is
selected from the group consisting of hydrogen, --OH, C1 to C12
alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate and sulfonamide, and [0408] for each A
and A',

[0408] ##STR00143## may be attached to either side of A and A' so
that in the example of A or A' being

##STR00144## the

##STR00145## can be any of:

##STR00146## [0409] B' is

[0409] ##STR00147## wherein, [0410] B' is optionally substituted
with between 1 and 4 substituents, each independently selected from the
group consisting of --OH, --CN, --NO2, halogen, C1 to C12
alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide, amino and oxo, [0411]
Xa is chosen from the group consisting of --CH2--,
--CH2--CH2--, --CH═CH--, --O--, --S--, --S(═O)2--,
--CH2--O--, --NR1-- and --CH2--NR1-- wherein R1
is chosen from the group consisting of hydrogen, C1 to C8
alkyl, and C1 to C8 heteroalkyl, and [0412] Xb is either C
or N; [0413] X and X' are each either present or absent and if present,
independently selected from the group consisting of a bond, --CH2--,
--CH2--CH2--, --CH═CH--, --O--, --S--, --S(O)2--,
--CH2O--, --CH2S--, --CH2S(O)2-- and
--CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl [0414]
Y and Y' are each independently carbon or nitrogen; and [0415] Z and Z'
are independently selected from the group consisting of hydrogen, C1
to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8 and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t--R8, wherein,
[0416] U is selected from the group consisting of --C(O)--, --C(S)-- and
--S(O)2--, [0417] each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, [0418] R8 is selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81 and --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, [0419] optionally, R7 and
R8 together form a 4-7 membered ring, [0420] each t is independently
0, 1, 2, 3, or 4, and [0421] u is 0, 1, or 2.

[0422] The compounds of the present invention include pharmaceutically
acceptable salts of VII as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0423] In a twelfth aspect of the invention, compounds have formula VIII:

##STR00148##

wherein: [0424] B' is selected from the group consisting of

##STR00149##

##STR00150##

[0424] optionally includes 1 or 2 nitrogens as heteroatoms; [0425] each
Ra is independently selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; [0426] r is 0, 1, 2, 3 or 4; [0427] X and X' are
each independently selected from the group consisting of a bond,
--CH2, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl; [0428] each
R8 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81, --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl; and [0429] each R4 is
independently selected from the group consisting of hydrogen, C1 to
C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl and aralkyl.

[0430] The compounds of the present invention include pharmaceutically
acceptable salts of IX as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0431] In a thirteenth aspect of the invention, compounds have formula IX:

##STR00151##

wherein: [0432] B' is selected from the group consisting of

##STR00152##

##STR00153##

[0432] optionally includes 1 or 2 nitrogens as heteroatoms; [0433] each
Ra is independently selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; [0434] r is 0, 1, 2, 3 or 4; [0435] X and X' are
each independently selected from the group consisting of a bond,
--CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl; [0436] each
R8 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81, --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl; and [0437] each R4 is
independently selected from the group consisting of hydrogen, C1 to
C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl and aralkyl.

[0438] The compounds of the present invention include pharmaceutically
acceptable salts of IX as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0439] In a fourteenth aspect of the invention, compounds have formula X:

##STR00154##

wherein: [0440] B' is selected from the group consisting of

##STR00155##

##STR00156##

[0440] optionally includes 1 or 2 nitrogens as heteroatoms; [0441] each
Ra is independently selected from the group consisting of --OH,
--CN, --NO2, halogen, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,
sulfonamide and amino; [0442] r is 0, 1, 2, 3 or 4; [0443] X and X' are
each independently selected from the group consisting of a bond,
--CH2--, --CH2--CH2--, --CH═CH--, --O--, --S--,
--S(O)1-2--, --CH2O--, --CH2S--, --CH2S(O)1-2--
and --CH2N(R1)--, wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,
alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl; [0444] each
R8 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81, --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl; and [0445] each R4 is
independently selected from the group consisting of hydrogen, C1 to
C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl and aralkyl.

[0446] The compounds of the present invention include pharmaceutically
acceptable salts of X as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0447] In a fifteenth aspect of the invention, compounds have formula XI:

##STR00157##

wherein: [0448] each Ra is independently selected from the group
consisting of --OH, --CN, --NO2, halogen, C1 to C12 alkyl,
C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino; [0449] r is 0, 1,
2, 3 or 4; [0450] Xa is chosen from the group consisting of
--CH2--, --CH2--CH2, --CH═CH--, --O--, --S--,
--S(═O)2--, --CH2--O--, --NR1-- and
--CH2--NR1-- wherein R1 is chosen from the group
consisting of hydrogen, C1 to C8 alkyl, and C1 to C8
heteroalkyl, [0451] each R8 is independently chosen from the group
consisting of hydrogen, C1 to C8 alkyl, C1 to C8
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl,
--C(O)--R81, --C(S)--R81, --C(O)--O--R81,
--C(O)--N--R812, --S(O)2--R81,
--S(O)2--N--R812, wherein each R81 is independently
chosen from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl; and [0452] each R4 is independently selected from the
group consisting of hydrogen, C1 to C8 alkyl, C1 to
C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and
aralkyl.

[0453] The compounds of the present invention include pharmaceutically
acceptable salts of XI as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0454] In an additional aspect of the invention, compounds of formula XII
are provided:

##STR00158##

wherein, [0455] A and A' are independently selected from the group
consisting of a single bond,
--(CR2)n--C(O)--(CR2)p--,
--(CR2)n--O--(CR2)p--,
--(CR2)n--N(RN)--(CR2)p--,
--(CR2)n--S(O)k--N(RN)--(CR2)p--,
--(CR2)n--C(O)--N(RN)--(CR2)p--,
--(CR2)n--N(RN)--C(O)--N(RN)--(CR2)p--,
--(CR2)n--C(O)--O--(CR2)p--,
--(CR2)n--N(RN)--S(O)k--N(RN)--(CR2)p--
- and --(CR2)n--N(RN)--C(O)--O--(CR2)p-- and a
heteroaryl group selected from the group consisting of

[0455] ##STR00159## wherein: [0456] X1 is CH2, NH, O or
S, [0457] Y1, Y2 and Z1 are each independently CH or N,
[0458] X2 is NH, O or S, [0459] V is --CH2--CH2--,
--CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,

[0459] ##STR00160## optionally includes 1 or 2 nitrogens as
heteroatoms on the phenyl residue, [0460] the carbons of the heteroaryl
group are each independently optionally substituted with a substituent
selected from the group consisting of --OH, --CN, --NO2, halogen,
C1 to C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, [0461]
the nitrogens, if present, of the heteroaryl group are each independently
optionally substituted with a substituent selected from the group
consisting of --OH, C1 to C12 alkyl, C1 to C12
heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, [0462] a and b are independently 1, 2, or 3, [0463] c and d
are independently 1 or 2, [0464] n and p are independently 0, 1, 2 or 3,
[0465] k is 0, 1, or 2, [0466] each R is independently selected from the
group consisting of hydrogen, --OH, --CN, --NO2, halogen, C1 to
C12 alkyl, C1 to C12 heteroalkyl, cycloalkyl, heterocycle,
aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino, [0467] each
RN is independently selected from the group consisting of hydrogen,
--OH, C1 to C12 alkyl, C1 to C12 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,
alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide, and [0468] wherein for each A and A', B may be attached to
either side of A and A' so that in the example of A or A' being

[0468] ##STR00161## the A-B-A' can be any of:

##STR00162## [0469] B is selected from the group consisting of

[0469] ##STR00163## ##STR00164## wherein:

##STR00165## [0470] is a divalent aryl or heteroaryl group which
may be polycyclic with varying connective patterns; [0471] V is
--CH2--, --CH2--CH2--, --CH═CH--, --N═CH--,
(CH2)a--N(RN)--(CH2)b-- or
--(CH2)a--O--(CH2)b--, wherein a and b are
independently 0, 1, 2, or 3 with the proviso that a and b are not both 0;
[0472] X1 is CH2, NH, O or S, [0473] each Y1 is
independently CH or N, [0474] each r and s is independently 0, 1, 2, 3 or
4; [0475] each Ra is independently selected from the group
consisting of --OH, --CN, --NO2, halogen, C1 to C12 alkyl,
C1 to C12 heteroalkyl, cycloalkyl, heterocycle, aryl,
heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl,
substituted sulfonyl, sulfonate, sulfonamide and amino; and [0476] each
Rb is independently selected from the group consisting of
C1-C12 alkyl, hydroxyl, halogen and oxo; [0477] Rc,
Rd, Re, and Rf are each independently selected from the
group consisting of: hydrogen, C1 to C8 alkyl, C1 to
C8 heteroalkyl, aralkyl and a 4- to 8-membered ring which may be
cycloalkyl, heterocycle, heteroaryl or aryl, wherein, [0478] each hetero
atom, if present, is independently N, O or S, [0479] each of Rc,
Rd, Re, and Rf may optionally be substituted by C1 to
C8 alkyl, C1 to C8 heteroalkyl, aralkyl, or a 4- to
8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or aryl
and wherein each heteroatom, if present, is independently N, O or S,
[0480] Rc and Rd are optionally joined to form a 4- to
8-membered heterocycle which is optionally fused to another 3- to
6-membered heterocycle or heteroaryl ring, and [0481] Re and Rf
are optionally joined to form a 4- to 8-membered heterocycle which is
optionally fused to another 3- to 6-membered heterocycle or heteroaryl
ring; [0482] Y and Y' are each independently carbon or nitrogen; and
[0483] Z and Z' are independently selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--NR7--(CR42)t--R8,
--U--(CR42)t--R8, and
--[U--(CR42)t--NR5--(CR42)t]u--U--
-(CR42)t--O--(CR42)t--R8, wherein,
[0484] U is selected from the group consisting of --C(O)--, --C(S)--, and
--S(O)2--, [0485] each R4, R5 and R7 is independently
selected from the group consisting of hydrogen, C1 to C8 alkyl,
C1 to C8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl
and aralkyl, [0486] R8 is selected from the group consisting of
hydrogen, C1 to C8 alkyl, C1 to C8 heteroalkyl,
cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, --C(O)--R81,
--C(S)--R81, --C(O)--O--R81, --C(O)--N--R812,
--S(O)2--R81, and --S(O)2--N--R812, wherein each
R81 is independently chosen from the group consisting of hydrogen,
C1 to C8 alkyl, C1 to C8 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl and aralkyl, [0487] optionally, R7 and
R8 together form a 4-7 membered ring, [0488] each t is independently
0, 1, 2, 3, or 4, and [0489] u is 0, 1, or 2.

[0490] The compounds of the present invention include pharmaceutically
acceptable salts of XII as well as an optically pure enantiomer, racemate
or diastereomeric mixtures thereof.

[0491] The compounds of the invention are prepared by synthetic routes and
procedures that are illustrated in the various synthetic schemes below.
The synthetic routes shown in schemes below are disclosed for the purpose
of illustration and are not meant to be interpreted as limiting the
processes to make the embodied compounds by any other methods. It will be
appreciated by those skilled in the art that a number of methods are
available for the preparation of the compounds of the present invention.
These compounds may be prepared by processes which include processes
known in the chemical art for the production of structurally analogous
compounds or by a novel process described herein. One of the general
strategies includes building the central scaffold followed by gradual
functional group transformations of the two ends either simultaneously.
In order to differentially functionalize the two ends, some orthogonal
functional group protection and deprotection strategies are used (T. W.
Greene & P. G. M. Wutts, Protective Groups in Organic Synthesis, John
Wiley & Sons, 3rd edition, 1999). Another synthetic strategy entails
the construction of the two halves of the molecule separately and
coupling them toward the end of the synthesis. The cross coupling
techniques employ conditions such as the Sonogashira, Suzuki-Miayura, or
Stille reaction for connecting carbon-carbon bonds. For scaffold cores
linked via a carbon-nitrogen bond, their syntheses typically utilize a
nucleophilic aromatic substitution reaction, a Buchwald or a Ma cross
coupling reaction. The functional groups, typically amines and carboxyl
groups on either ends of the cores are generally orthogonally protected
to allow for selective further manipulations as needed.

[0540] Schemes 1-1 and 1-2 illustrate the various methods of preparing
aryl-carbocyclic central scaffolds (Bs) and how the two ends of the
molecule can be differentially constructed in order to allow for
selective functionalization of either end of the molecule.

##STR00167##

##STR00168## ##STR00169##

[0541] Scheme 1-3 outlines the preparation of core structures connected
through a carbon-nitrogen bond. The nitrogen arylation is achieved using
one of the several methods. In one embodiment, the acetophenone moiety
and the V group in A-17 can be sequentially converted to a bromoketone as
in A-18 for further introduction of the A-19 moiety. The coupling between
A-15 and A-16 to A-17 represents a nucleophilic aromatic substitution
method. Other methodologies employed include Buchwald or Ma couplings (J.
Org. Chem. 2005, 70, 164), such as the coupling of A-15 with A-20 to B-6,
A-15 with A-22 to B-7, A-21 with A-22 to B-8. When V is a carboxylate, it
can be extended via an amide linkage. Taking B-6 as an example, the
carboxylate can undergo a Curtis rearrangement to an amine, which in turn
can be transformed to an amide (B-6 to B-9). Alternatively, the
carboxylate can be hydrolyzed and converted to B-10 when reacts with a
protected form of pyrrolidin-2-ylmethanamine. The methodologies outlined
in this scheme are further depicted in other schemes described herein.

##STR00170##

[0542] Scheme 1-4 illustrates some of the ways for further functional
group transformations using scaffold B-1 as an example. Starting from a
properly protected B-1, the nitrogen protecting groups P and P' can be
removed simultaneously to give B-1a. When B-1a is treated together a
suitably protected amino acid under standard peptide coupling conditions,
such as HATU and a tertiary amine base, e.g. Hunig's base, the doubly
coupled product B-1b is obtained. Typically, P refers to a protecting
group such as Boc-, Cbz-, Troc-, etc. P can also be other alkyl, acyl,
alkoxylcarbonyl, alkylaminocarbonyl groups that are intended for this
position. When P is one of the removable groups, upon its removal, the
free the amino group can be further derivatized to B-1c. The definition
of Cap group is P and P'. The protecting groups P and P' can be removed
selectively to free one of the two amino groups in B-1 as in the case of
B-1 to B-1d. These skilled in the art will understand that the P' group
can be deprotected while the P group is preserved to give an alternative
structure such as B-1d. The free amino group of B-1d is coupled with
another properly functionalized amino acid to give B-1e. When this
process of selective deprotection and functionalization is repeated,
compound B-1f is obtained. The newly introduced amino acid in B-1f can be
the same as the residue on the left-hand side of the molecule or can be a
different one. From B-1f, a variety of compounds (with a general formula
of B-1g) are prepared with differentially functionalized end pieces.

[0543] In another embodiment, several key intermediates used in the
construction of claimed scaffolds are depicted in the following schemes.

##STR00171##

[0544] Scheme 1-5 using an L-proline-based structure as an example
describes the synthesis of several key imidazole intermediates that are
used for the construction of various more advanced intermediates in this
invention. (References: a. Polyhedron 2005, 24, 2625, b. WO2008/021927).
The readily available L-prolinaldehyde is converted to imidazole A-24 by
reacting with glyoxal in the presence of ammonium hydroxide. The
monohalogenation (bromination or iodination) is best achieved via a
two-step sequence, i.e. non-selective dihalogenation followed by a
selective removal of one of the two halogen atoms to A-26. To facilitate
the further functionalization, the imidazole moiety is preferably
protected with SEM or other protecting groups. The protection process
does generate a mixture of regioisomers of the protecting group. However,
such a mixture does not usually affect the reactivity of the
intermediates toward further reaction and will become one compound upon
the removal of the protecting group. The iodo- or bromo-imidazole
intermediate A-27 is used converted to is the corresponding borate A-28
under the conditions shown, or using conditions that are known to promote
similar transformations. When the same intermediate A-27 is subjected to
Sonogoshira coupling conditions, the acetylene compound A-28 is obtained
after subsequent treatment with base. The use of intermediate as an
alternative method of synthesizing arylimidazole intermediates such as
A-1 and B-3 is illustrated in Scheme 1-1. These versatile building blocks
are used in many other manners as will be shown in the schemes to follow.

##STR00172##

[0545] In another embodiment, the aryl-imidazole and benzoimidazole
building blocks are synthesized using the route described in Scheme 1-6
(Ref. J. Med. Chem. 2008, 51, 5109; 2006, 49, 3774; and 2002, 45, 5556).
Those in the art shall recognize that the phenyl, the proline and the
protecting group on nitrogen may be replaced in order to achieve the
desired functionality at a given position.

##STR00173##

[0546] In another embodiment, the building blocks used in Scheme 1-1 for
the synthesis of scaffolds such as B-1 to B-4 and others are synthesized
using routes described in Scheme 1-7. The preparation of A-1a starts with
the dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate, one of the methyl
ester group is selectively hydrolyzed to the acid, which in turn is
converted to a bromo group to give methyl
4-bromobicyclo[2.2.2]octane-1-carboxylate. A Friedel-Crafts reaction
between methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate and a
substituted benzene yields A-1a (Ref. J. Org. Chem. 1970, 35, 917).
Compound A-1b is prepared similarly. Another method to prepare the
cyclohexyl-containing compounds such as A-1b and A-1b' is through a cross
coupling reaction between vinyltrifolate and a phenylboronate (or a
boronic acid). The letter V represents a carboxylate group, such as an
ethoxylcarbonyl, or a protected amino group, or can be another functional
group that can be further functionalized. Following the coupling step,
the resulted styrenyl group can be preserved (A-1b') or can be saturated
under hydrogenation condition to give A-1b. The cyclopentyl analog A-1c
may be made by similar route. The four-carbon analog is made in sequence
as shown.

[0547] Synthesis of Example Compounds

[0548] The examples below provide exemplary synthetic methods for the
preparation of the compounds of the present invention. One of skill in
the art will understand that additional methods are also useful. The
compounds of the invention can be made using conventional organic
synthesis using starting materials, reagents and reactions well known in
the art.

[0549] Reagents and solvents used below can be obtained from commercial
sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). 1H-NMR
spectra were recorded on a Bruker 400 MHz or 500 MHz NMR spectrometer.
Significant peaks are tabulated in the order: multiplicity (s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet),
coupling constant(s) in Hertz (Hz) and number of protons. Electrospray
spray ionization (ESI) mass spectrometry analysis was conducted on a
Hewlett-Packard 1100 MSD electrospray mass spectrometer using the HP1 100
HPLC for sample delivery. Mass spectrometry results are reported as the
ratio of mass over charge, followed by the relative abundance of each ion
(in parentheses) or a single m/z value for the M+H (or, as noted, M-H)
ion containing the most common atomic isotopes. Isotope patterns
correspond to the expected formula in all cases. Normally the analyte was
dissolved in methanol at 0.1 mg/mL and 5 microliter was infused with the
delivery solvent into the mass spectrometer, which scanned from 100 to
1500 daltons. All compounds could be analyzed in the positive ESI mode,
using an acetonitrile/water gradient (10%-90%) acetonitrile in water with
0.1% formic acid as delivery solvent. The compounds provided below could
also be analyzed in the negative ESI mode, using 2 mM NH4OAc in
acetonitrile/water as delivery solvent. Enantiomeric purity was
determined using a Hewlett-Packard Series 1050 system equipped with a
chiral HLPC column (ChiralPak AD, 4.6 mm×150 mm) and isocratic
elution using 5:95 isopropanol-hexane as a mobile phase.

[0550] The compounds were named using ChemDraw program from Cambridge Soft
Inc.

[0553] Step b. A sample of compound 1 (1.0 g, 2.82 mmol) in
dichloromethane was treated with excess 4N HCl in dioxane. At the
completion of removal of Boc group as indicated by LCMS, solvents were
removed and the residue was dried under vacuum. This material was taken
up in acetonitrile (6 mL) and treated with tert-butyl
(1H-pyrazol-1-yl)methylenedicarbamate (2) (1.01 g, 3.2 mmol) and DIPEA
(0.60 g, 4.65 mmol) at rt overnight. The solvents were evaporated off and
the crude product was purified by silica gel column chromatography with a
gradient eluent consisting various ratio of EtOAc and hexanes to give
compound 3 (0.59 g, 71% yield).

[0554] Step c. A solution of 3 (1.34 g, 2.69 mmol, from combined runs) in
THF (5 mL) was treated with excess 4N HCl in dioxane at rt overnight.
Solvents were removed by evaporation, and residue was further dried under
high vacuum. A portion of this de-Boc material (0.3 g, 1.0 mmol) was
taken up in THF (4 mL) and water (0.34 mL). To this mixture was added
K2CO3 (0.27 g, 2.02 mmol) followed by bromoketone compound 4
(0.33 g, 1.01 mmol, prepared following published procedures). The entire
mixture was heated at reflux overnight. After cooling, the reaction
mixture was added CH2Cl2 and washed with H2O and brine,
respectively. After drying over Na2SO4, the solvent was removed
and the residue was purified by silica gel column chromatography, eluted
with 1-3% MeOH in EtOAc to afford 5 (0.32 g).

[0556] Step e. A solution of compound 6 (0.640 g, 1.1 mmol) in dioxane (24
mL) and water (2.4 mL) was sequentially added (S)-tert-butyl
2-(5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidi-
ne-1-carboxylate (1.10 g, 2.22 mmol), NaHCO3 (0.37 g, 3.66 mmol), and
Pd(dppf)Cl2.CH2Cl2 (90 mg, 0.11 mmol) at rt under an
atmosphere of Ar. After stirring at 80° C. overnight under an
atmosphere of Ar, the reaction mixture was diluted with EtOAc (100 mL).
The organic layer was isolated, washed with brine, and dried with
anhydrous Na2SO4. The solvent was removed and the residue was
purified by silica gel column chromatography to give compound 8 (0.2 g
mg) as a yellow solid.

[0557] Step f. A sample of compound 8 (34 mg) was treated 4N HCl in
dioxane (0.5 mL) at rt overnight to remove both the Boc group and the SEM
group. The Cbz group was removed under hydrogenolysis conditions (Pd/C,
H2).

[0559] Step a. Referring to Scheme 2-4, to a stirred solution of 1 (1 eq.,
0.2 M) in CH2Cl2 was added DIPEA (1.2 eq.). The reaction flask
was cooled with a water-ice bath, and TMSOTf (1.1 eq.) was slowly added
over a 10 min period. The reaction was stirred at 0° C. for 10
min, then at rt until silylation was complete, as determined by TLC (1.5
h). PTT (1M in THF, 1.05 eq) was added over 10 min. The reaction was
stirred at rt until bromination was complete, as judged by TLC (30 min).
The reaction was partitioned between CH2Cl2 and NaHCO3
with a 1/1 (v/v) ratio. The aqueous phase was extracted with
CH2Cl2 (2×). The combined organic layers were dried over
Na2SO4, filtered, and concentrated. The crude product 2 was
used without further purification.

[0560] Step b. To a stirred solution of 2 (1 eq., 0.3M) and N-Cbz-L-Pro-OH
(1 eq.) in MeCN was added DIPEA (1.2 eq.). The reaction was stirred at rt
for 16 h. The reaction was concentrated to dryness. The resulting crude
product was purified by silica gel column chromatography
(hexanes/EtOAc=100/0 to 70/30 (v/v), 5 step gradient) to provide 3.

[0561] Step c. To a stirred solution of 4 (1 eq, 0.3M) and N-Boc-L-Pro-OH
(1 eq.) in MeCN was added DIPEA (1.2 eq.). The reaction was stirred at rt
for 16 h. The reaction was concentrated to dryness. The resulting crude
product was purified by silica gel flash column chromatography
(hexanes/EtOAc=100/0 to 70/30 (v/v), 5 step gradient) to provide 5.

[0562] Step d. A stream of nitrogen was bubbled through a solution of 5 (1
eq., 0.3M) in o-xylene in a sealable reaction tube for 10 min.
NH4OAc (10 eq.) was added to the solution. The reaction tube was
sealed and placed in a 150° C. oil bath. The reaction was stirred
at this temperature for 1 h then cooled to rt. The reaction tube was
carefully opened, and its contents partitioned between aqueous
Na2CO3 and CH2Cl2/MeOH (10/1 (v/v)) with a 1:1 (v/v)
ratio. The layers were separated, and the aqueous phase was extracted
with CH2Cl2/MeOH (10/1) until the extracts were free of any
uv-active component (as determined by TLC). The combined organic layers
were dried over Na2SO4, filtered, and concentrated. The
resulting crude product was purified by silica gel column chromatography
(hexanes/EtOAc=50/50, 20/80, and 0/100, then MeOH/EtOAc=1/99 (v/v)) to
provide 6.

[0563] Step e. To a solution of 6 (1 eq.) in EtOH/AcOH (1/1, v/v) was
added Pd(OH)2 on carbon (10%). After sealing the reaction flask with
a rubber septum, the system was evacuated and backfilled with 1 atm
H2 (2×). The vigorously stirred reaction was stirred at rt
under H2 (1 atm) for 16 h. The mixture was filtered through a pad of
CELITE®545 (pre-washed with EtOH), and the separated solids were
washed with EtOH (5×). The filtrate was concentrated to provide
crude 7. Residual AcOH was removed by dissolving the crude product in
H2O then adjusting the pH to ˜13 with 2N aqueous NaOH. The
product was extracted with CH2Cl2 until the extracts were free
of 7. The crude product was used without further purification.

[0564] Step f. To a solution of 7 (1 eq., 0.3M) and 3 (1 eq.) in DMSO was
added DIPEA (1.2 eq). The reaction was stirred at rt for 4 h then at
30° C. for 16 h. The reaction was then partitioned between aqueous
Na2CO3 and CH2Cl2/MeOH (10/1 (v/v)) with a 1:1 (v/v)
ratio. The layers were separated, and the aqueous phase was extracted
with CH2Cl2/MeOH (10/1 (v/v)) until the extracts were free of
any UV-active component. The combined organic layers were dried over
Na2SO4, filtered, and concentrated by rotary evaporation. The
resulting crude product was purified by silica gel column chromatography
(hexanes/EtOAc=33/67 to 0/100 (v/v), 5 step gradient) to provide 8.

[0565] Step g. A stream of nitrogen was bubbled through a solution of 8 (1
eq, 0.3M) in o-xylene in a sealable reaction tube for 10 min. NH4OAc
(10 eq) was added to the solution. The reaction tube was sealed and
placed in a 150° C. oil bath. The reaction was stirred at this
temperature for 1 h then cooled to rt. The reaction tube was carefully
opened, and its contents were partitioned between aqueous
Na2CO3 and CH2Cl2/MeOH (10/1 (v/v)) with a 1:1 (v/v)
ratio. The layers were separated, and the aqueous phase was extracted
with CH2Cl2/MeOH (10/1 (v/v)) until the extracts were free of
any UV-active component. The combined organic layers were dried over
Na2SO4, filtered, and concentrated by rotary evaporation. The
resulting crude product was purified by silica gel flash column
chromatography (hexanes/EtOAc=25/75 to 0/100 (v/v), then MeOH/EtOAc 1/99
to 3/97 (v/v)) to provide 9.

[0566] Step h. To a solution of 9 (1 eq) in absolute EtOH was added Pd on
carbon (10%,

[0567] 50% H2O). After sealing the reaction flask with a rubber
septum, the system was evacuated and backfilled with 1 atm H2
(2×). The vigorously stirred reaction was stirred at rt under
H2 (1 atm) for 4 h. The mixture was filtered through a pad of
CELITE®545 (pre-washed with EtOH), and the separated solids were
washed with EtOH (5×). The filtrate was concentrated to provide
crude 10 that was used without further purification.

[0568] Step i. To a stirred solution of 10 (1 eq, 0.1M) and N-Moc-D-Phg-OH
(1 eq.) in DMF, DMTMM (1 eq.) and DIPEA (1 eq.) were sequentially added.
The reaction was stirred at rt for 1 h and partitioned between aqueous
Na2CO3 and CH2Cl2/MeOH (10/1) with a 1/1 (v/v) ratio.
The layers were separated, and the aqueous phase was extracted with
CH2Cl2/MeOH (10/1) until the extracts were free of any
uv-active component. The combined organic layers were dried over
Na2SO4, filtered, and concentrated by rotary evaporation.
Residual DMF was removed by bulb-to-bulb distillation using gentle
heating. The remaining crude product was purified by silica gel column
chromatography (hexanes/EtOAc=25/75, 10/90, 0/100 (v/v), then
MeOH/EtOAc=1/99 to 3/97 (v/v)) to provide 11.

[0569] Step j. Compound 11 (1 eq.) was treated with THF (7 mL/mmol 11)
followed by slow addition of 4N HCl in dioxane (14 mL/1 mmol of 11). The
reaction was stirred at rt for 2 h. The reaction mixture was concentrated
to dryness to provide 12.

[0570] Step k. To a stirred solution of 12 (1 eq, 0.1M) and N-Boc-D-Phg-OH
(1 eq.) in DMF were sequentially added DMTMM (1 eq.) and DIPEA (1 eq.).
The reaction was stirred at rt for 1 h. The crude reaction mixture was
purified on a C18-Luna preparative HPLC column (H2O-MeCN, 0.1%
HCO2H) to give compound 13 as a white solid.

[0571] Step l. Compound 13 (1 eq.) was treated with THF (7 mL/mmol)
followed by slow addition of 4N HCl in dioxane (14 mL/1 mmol of 13). The
reaction was stirred at rt for 3 h. The reaction mixture was concentrated
to dryness to provide 14.

[0573] Step a. Referring to Scheme 2-6 to a suspension of AlCl3 (19.5
g, 146 mmol) in CS2 (40 mL) at -78° C. was added acetyl
chloride (10.4 mL, 146 mmol) slowly over 10 min. The mixture was stirred
vigorously for 15 min and cyclohexene (10 g, 122 mmol) was added dropwise
over 20 min. The mixture was stirred below -20° C. for 30 min. The
solvent was removed and the residue was re-dissolved in benzene. The
mixture was heated at 40-50° C. 3-4 h, cooled to rt and poured
into a mixture of ice and HCl (1N). The organic layer was collected, and
aqueous layer was extracted with ethyl acetate (3×). The combined
organic layers were concentrated and purified on a column (hexane:ethyl
acetate, 8:2) to give 1-(4-phenylcyclohexyl)ethanone (A1) (9 g, 37%
yield).

[0574] Step b. To a suspension of AlCl3 (5.9 g, 54 mmol) in DCM (200
mL) at 0° C. was added 1-(4-phenylcyclohexyl)ethanone (9 g in
DCM), and acetyl chloride (10.4 mL, 146 mmol) dropwise over 30 min. The
mixture was stirred to rt for 15 min. and heated at 45° C. for 4
h. After being cooled to rt, the mixture was poured it into ice-HCl (1N).
The organic layer was collected, and the aqueous layer was extracted with
ethyl acetate (3×). The combined organic layers were combined,
concentrated and purified on column (hexane:ethyl acetate, 8:2) to give
1-(4-(4-acetylcyclohexyl)phenyl)ethanone (A2) as a mixture of two isomers
(5 g, 46% yield).

[0576] Step d. To a solution of N-Cbz-L-Pro-OH (1.36 g, 5.47 mmol) in
acetonitrile (10 mL) was added triethyl amine (762 μL, 5.47 mmol) and
2-bromo-1-(4-(4-(2-bromoacetyl)cyclo hexyl)phenyl)ethanone (A3) (1 g,
2.49 mmol) in acetonitrile. The reaction mixture was stirred at rt
overnight. The solvent was removed and product was diluted with ethyl
acetate (3×), washed with NaHCO3 (100 mL) and brine, and dried
with Na2SO4. After removal of the solvent, the crude product
(S)-1-benzyl
2-(2-(4-(4-(2-((S)-1-(benzyloxycarbonyl)pyrrolidine-2-carbonyloxy)acetyl)-
cyclohexyl)phenyl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (A4) (2.5 g)
was used for the next step directly.

[0577] Step e. A solution of (S)-1-benzyl
2-(2-(4-(4-(2-((S)-1-(benzyloxycarbonyl)pyrrolidine-2-carbonyloxy)acetyl)-
cyclohexyl)phenyl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (A4) (3.0 g,
4.06 mmol) in o-xylene (25 mL), ammonium acetate (3.76 g, 48.7 mmol) and
diisopropylethylamine (48.7 mmol) was placed in a pressure resistant
tube. The tube was sealed and heated to 140° C. for 4 h, cooled to
rt. The volatile component was removed in vacuo and the residue was
partitioned between water and CH2Cl2. The organic phase was
dried, filtered and concentrated in vacuo. The resulting crude material
was purified by a flash chromatography (CH2Cl2/MeOH=9/1 (v/v))
to provide (S)-benzyl
2-(4-(4-(4-(4-((S)-1-(benzyloxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-2-yl-
)phenyl)cyclohexyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (A5) as
yellow residue (200 mg).

[0578] Step f. (S)-benzyl
2-(4-(4-(4-(4-((S)-1-(benzyloxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-2-yl-
)phenyl)cyclohexyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (A5) (200
mg) and Pd/C (20 mg) in MeOH (20 mL) was purged with H2. The
reaction was stirred under hydrogen balloon for 48 h, filtered on
CELITE® and concentrated. The residue
2-((S)-pyrrolidin-2-yl)-4-(4-(4-(4-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl-
)phenyl)cyclohexyl)-1H-imidazole (A6) was directly used for next step
without further purification.

[0580] Step a. Referring to Scheme 2-7 to a suspension of AlCl3 (1.58
g, 12 mmol) in DCM (30 mL) at -78° C. was added
1-(4-phenylcyclohexyl)ethanone (A1') (1 g in DCM, 5.0 mmol), and
bromoacetyl bromide (0.65 mL, 7.5 mmol) dropwise over 10 min. The mixture
was stirred to rt for 15 min and heated at 40-50° C. for 3 h,
cooled to rt and poured into a mixture of ice and HCl (1N). The organic
layer was collected, and the aqueous layer was extracted with ethyl
acetate (3×). The combined organic layers were concentrated on
rotovap and purified silica gel column chromatography (Hexanes/EtOAc=8/2
(v/v)) to give the desired trans-isomer A2' (1 g, 62% yield) along with a
small amount of cis-isomer.

[0582] Step c. To a solution of A3' (20.0 g, 40.7 mmol) and
diethylisopropylamine (20 mL) in DCM (200 mL) in a round bottom flask was
added trimethylsilyl trifluoromethanesulfonate (TMSOTf, 20 mL, 122 mmol)
at -78° C. The reaction was stirred at rt overnight. To the
solution was added a solution of phenyltrimethylammonium tribromide (PTT,
16.8 g, 45 mmol) in THF (50 mL). The reaction was stirred at rt 2 h and
quenched with saturated NaHCO3 solution. The mixture was partitioned
between water and CH2Cl2 (3×), and the organic layers
were washed with brine, dried, filtered and concentrated in vacuum. The
resulting crude material was purified by silica gel column chromatography
(Hexanes/EtOAc=1/1 (v/v)) to provide A4' as yellow residue (17 g, 73%
yield).

[0583] Using similar procedure as for compound A3' from A2', compound A5'
was prepared from the corresponding bromide A4' in 80% yield.

[0584] Step d. To a solution of A5' (2.5 g, 3.5 mmol) in o-xylene (25 mL)
in a sealed tube was added ammonium acetate (4.1 g, 53 mmol). The mixture
was sealed and heated at 140° C. for 3 h and then cooled to rt.
The volatile component was removed in vacuo, and the residue was
partitioned between H2O and CH2Cl2, and the organic phase
was dried, filtered and concentrated in vacuo. The resulting crude
material was purified by silica gel column chromatography
(CH2Cl2/MeOH=9/1 (v/v)) to provide A6' as a yellow solid (250
mg, 10% yield).

[0585] Step e. Following the deprotection and amide formation operations
described for similar systems and repeated the process twice, the
differentially functionalized compound A8' was obtained. LC-MS (ESI): m/z
789 (M+H)+.

[0588] Step c. To a solution of methyl
3-(4-acetylphenyl)cyclobutanecarboxylate (A3) (6.56 g, 28.2 mmol) in
methylene chloride (250 mL) at 0° C. was added PTT (10.6 g, 28.2
mmol) and the reaction mixture was stirred at rt overnight. The reaction
was quenched with NaHCO3 (100 mL), washed with brine, and dried with
Na2SO4. After removal of the solvent, crude product A4 (7.2 g,
82% yield) was directly used for the next step.

[0589] Step d. A solution of crude methyl
3-(4-(2-bromoacetyl)phenyl)cyclobutanecarboxylate (A4) (8.8 g, 28.3
mmol), N-Boc-L-Pro-OH (6.7 g, 31.2 mmol) and triethylamine (4.34 mL) in
CH3CN was stirred for 2 h. At the completion of reaction, the
volatile components were removed in vacuo, and the residue was
partitioned between H2O and CH2Cl2. The organic phase was
dried, filtered and concentrated in vacuo. The residue was purified by
silica gel column chromatography to provide (S)-1-tert-butyl
2-(2-(4-(3-(methoxycarbonyl)cyclobutyl)phenyl)-2-oxoethyl)pyrrolidine-1,2-
-dicarboxylate (A5) as a colorless oil (10.6 g, 84% yield).

[0590] Step e. A mixture of ketoester (S)-1-tert-butyl
2-(2-(4-(3-(methoxycarbonyl)cyclobutyl)phenyl)-2-oxoethyl)pyrrolidine-1,2-
-dicarboxylate (A5) (3.7 g, 8.76 mmol) and NH4OAc (6.75 g, 87.6 mmol)
in o-xylenes (10 mL) was heated in a sealed tube at 140° C. for 1
h. The volatile component was removed in vacuo, and the residue was
partitioned between H2O and CH2Cl2. The organic phase was
dried, filtered and concentrated in vacuo. The resulting crude material
was purified by silica gel column chromatography to provide
(S)-tert-butyl
2-(4-(4-(3-(methoxycarbonyl)cyclobutyl)phenyl)-1H-imidazol-2-yl)pyrrolidi-
ne-1-carboxylate (A6) as a colorless oil (1.76 g, 47.4% yield).

[0591] Step f. To a solution of the compound (S)-tert-butyl
2-(4-(4-(3-(methoxycarbonyl)cyclobutyl)phenyl)-1H-imidazol-2-yl)pyrrolidi-
ne-1-carboxylate (A6) (1.76 g, 41.5 mmol) in THF (10 mL) and MeOH (10 mL),
LiOH (1M, 10.0 mL) was added at 0° C. After 30 min of stirring,
the reaction was quenched with saturated solution of NH4Cl,
extracted with EtOAc, dried over Na2SO4, and concentrated to
obtain the crude product
(S)-3-(4-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phe-
nyl)cyclobutanecarboxylic acid (A7) (1.4 g, 82.4% yield), which was used
without further purification.

[0593] Step h. To a solution of (S)-tert-butyl
2-(4-(4-(3-(benzyloxycarbonylamino)
cyclobutyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (A8) (449
mg, 0.87 mmol) in methanol (10 mL) was added 10% Pd/C (50 mg) and the
mixture was stirred overnight under H2 atmosphere in a balloon. The
mixture was filtrated and concentrated to obtain the crude product
(S)-tert-butyl
2-(4-(4-(3-aminocyclobutyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxy-
late (A9) (330 mg, 99% yield) without further purification.

[0595] Step j. To a solution of (S)-tert-butyl
2-(3-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-1-imidazol-4-y-
l)phenyl)cyclobutylcarbamoyl)pyrrolidine-1-carboxylate (A10) (100 mg,
0.173 mmol) in THF (8 mL), 4N HCl in dioxane (2 mL) was added slowly at
rt. After stirring for 1.5 h, the solvent was removed to give
(S)-N-(3-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)cyclobutyl)p-
yrrolidine-2-carboxamide (A11) as an HCl salt. The white solid was used
for the next step without further purification.

[0597] Additional examples of formula IX bearing varying capping groups
were prepared following procedures described below, such as in the
synthesis of compound A14, shown in Scheme 3-2.

[0598] Step a. A sample of the product from Scheme 3-1, tert-butyl
(R)-2-((S)-2-(3-(4-(2-((S)-1-((R)-2-(tert-butoxycarbonyl
amino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)cyclobutyl-
carbamoyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (A13) (222 mg,
0.262 mmol) in THF (10 mL) was treated with 4N HCl in dioxane (5 mL) at
rt for 8 h. At the completion of the reaction, solvent was removed and
the resulting white solid,
(5)-1-((R)-2-amino-2-phenylacetyl)-N-(3-(4-(2-((S)-1-((R)-2-amino-2-pheny-
lacetyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)cyclobutyl)pyrrolidine-2--
carboxamide (300 mg) was used for the next step without further
purification.

[0602] Step b. To a solution of freshly prepared LDA (132 mL of n-butyl
lithium, 2.5 M in hexane, 51 mL of diisopropylamine) in THF (anhydrous,
420 mL), DMPU (200 mL) at -78° C. was added a solution of A1 (60
g, 300 mmol) in THF (60 mL) at -78° C. After stirring for 40 min,
1-bromo-2-chloroethane (24.9 mL, 300 mmol) was added. After stirring for
another 20 min at -78° C., the dry ice-acetone bath was removed
and the reaction was slowly warmed up to rt. After stirring for an
additional hour, the reaction mixture was cooled back to -78° C.
and a solution of DMPU (200 mL) in THF (420 mL) was added. Another
portion of freshly prepared LDA (120 mL of n-butyl lithium, 2.5 M in
hexane, 47 mL of di-isopropylamine in THF (anhydrous, 420 ml)) was added
into the reaction mixture by cannula at -78° C. After stirring for
1.5 h at -78° C., the dry ice-acetone bath was removed and the
reaction was slowly warmed up to rt. After 5-6 h, the reaction was
quenched with saturated aqueous ammonium chloride (300 mL) and
concentrated. The residue was diluted with H2O (480 mL) and
extracted with ethyl acetate/hexane (1:5 (v/v), 3×360 mL). The
combined organic layers were washed with brine (500 mL) and then dried,
filtered, and concentrated. The resulting crude product was purified by
silica gel flash column chromatography (Hexanes/EtOAc=10/1 (v/v)) to
provide A2 (35 g).

[0603] Step c. To a solution of A2 (24.7 g) in MeOH (310 mL) was added
potassium hydroxide (6.12 g) in H2O (62 mL) at rt. The reaction was
warmed up to 95° C. and stirred overnight. The reaction was cooled
to rt and concentrated. The residue was diluted with H2O (1000 mL)
and extracted with ethyl acetate/hexane (1:10, 3×400 mL), which
provided recycled A2 (4.8 g) after concentration. The remaining aqueous
layer was acidified to pH=3 by concentrated HCl and then was extracted
with ethyl acetate/methanol (10:1 (v/v), 3×500 mL). The combined
organic layers were dried with sodium sulfate, filtered and concentrated
to provide A3 (17.8 g).

[0604] Step d. To a solution of A3 (17.8 g) in dibromomethane (1200 mL)
was added mercury(II) oxide at rt. The reaction was warmed up to
80° C. and bromine (6.0 mL) was added dropwise during 25 min.
After additional 3 h stirring, the reaction was cooled down to rt and
filtered through a pad of CELITE®, washed with dichloromethane,
concentrated to afford A4 (19.8 g). The crude product A4 was used without
further purification.

[0605] Step e. To a solution of A4 (19.8 g) in dichloromethane (500 mL) at
-20° C. was added aluminum chloride (43 g) in several portions.
The reaction was then warmed up to 0° C. After overnight stirring,
the reaction was poured into a mixture of ethyl acetate (800 mL), 1M HCl
(800 mL) along with some ice. After separating the ethyl acetate layer,
the aqueous layer was extracted with ethyl acetate (3×300 mL). The
combined organic layers were washed with brine, H2O, dried over
Na2SO4, filtered, and concentrated to afford A5 (19.2 g), which
was used without further purification.

[0606] Step f. To a solution of A5 (19.2 g) in dichloromethane (500 mL) at
-20° C. was added acetyl chloride (16.8 mL), followed by aluminum
chloride (43 g). The reaction was allowed to warm up to rt. After
overnight stirring, the reaction was poured into a mixture of ethyl
acetate (800 mL), 1M HCl (800 mL) along with some ice. After separating
the organic layer, the aqueous layer was extracted with ethyl acetate
(3×300 mL). The combined organic layers were washed with brine,
H2O, dried over Na2SO4, filtered, and concentrated to
afford A6 (24 g), which was used for next reaction without further
purification.

[0608] Step h. To a solution of A7 (14.8 g) in dichloromethane (800 mL)
was added oxalyl chloride (5.1 mL) at rt. DMF (209 μL) was added in
three portions over 4 h. The reaction was concentrated and re-dissolved
in dichloromethane (500 mL). The fresh made diazomethane (0.3M, 500 mL)
was added at 0° C. The reaction was slowly warmed up to rt. After
overnight stirring, the reaction was concentrated to obtain the crude A8
(17.8 g).

[0609] Step i. To a suspension of A8 (17.8 g) in acetic acid (250 mL),
hydrogen bromide (33% in acetic acid, 25 mL) was added dropwise at rt.
After stirring for an additional hour, the reaction was filtered though a
pad of CELITE®454, washed with ethyl acetate, concentrated to afford
the crude product, which was purified by silica gel flash column
chromatography (Hexanes/EtOAc=3/1 (v/v)) to provide A9 (18.5 g).

[0611] Step k. To a stirred solution of A10 (10 g) in CH2Cl2
(400 mL) was added DIPEA (3.4 mL). The reaction flask was cooled down to
-20° C. and TMSOTf (3.5 mL) was slowly added. The reaction was
warmed up to rt and stirred for 2 h, then cooled back to -20° C.
PTT (8.0 g) in THF (30 mL) was added over 10 min. The reaction was slowly
warmed up to rt and stirred overnight. The reaction was poured into a
mixture of dichloromethane (500 mL) and sodium disulfite (10% in
H2O, 500 mL). The organic layer was separated and washed with brine,
H2O, dried over sodium sulfate and concentrated to provide the crude
product, which was purified by silica gel flash column chromatography
(hexanes/EtOAc=4/1 (v/v)) to provide A11 (8.7 g).

[0613] Step m. A12 (6.5 g) was dissolved in xylene (100 mL) in a sealed
bottle. NH4OAc (14.5 g) and N,N-diisopropylethylamine (33 mL) were
added to the solution. The reaction tube was sealed and placed in an
140° C. oil bath. The reaction was stirred at this temperature for
1.5 h, then cooled to rt. The reaction tube was carefully opened, and
reaction mixture was diluted with dichloromethane. The combine organic
solution was washed with brine and H2O, dried over Na2SO4,
filtered, and concentrated. The resulting crude product was purified by
silica gel flash column chromatography (EtOAc/Acetone/28%
NH4OH=100/1/1 (v/v/v)) to provide A13 (3.0 g).

[0614] Step n. To a stirred solution of A13 (500 mg) in dichloromethane
(50 mL) was added trifluoroacetic acid (5 mL). After 3 h, the reaction
was concentrated to dryness to give a TFA salt, which was dissolved in
DMF (20 mL). To the solution were added DIEA (490 μL), N-Moc-D-Phg-OH
(98 mg) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride (DMTMM, 156 mg) subsequently. After one h stirring, the reaction
was diluted with H2O. The suspension was filtered through a pad of
CELITE®545 and washed with H2O. The filtrate cake was rinsed with
dichloromethane and concentrated to provide A14 (380 mg) without further
purification.

[0619] Step b. To a solution of 4 (0.95 g, 1.6 mmol) in DCM (32 mL) at
0° C. was add 4M HCl in dioxane. The mixture was stirred at
0° C. for 3 h and warmed to rt for 1 h. Solvent was removed to
give a white solid 5.

[0621] Step d. A mixture of 5 (400 mg, 1.0 mmol) and Pd/C (100 mg) in
methanol (12 mL) was degassed, and filled with hydrogen (60 psi). The
mixture was shaken for 16 h. The solution was filtered through a pad of
CELITE®545. The filtrate was concentrated to give a pale yellow solid
7.

[0637] Step e. To a solution of Intermediate 4 (310 mg, 0.95 mmol) and
chloroiodomethane (0.42 mL, 5.7 mmol) in THF (10 mL) was added LDA
(precooled to -78° C., freshly made from 1.75 mL of
diisoproylamine and 4.56 mL of 2.5 M n-BuLi in hexanes in 20 mL of THF)
at -78° C. via cannula for 20 min. The reaction mixture was
stirred for 2 h at -78° C. before it was quenched by dropwise
addition of 3 mL of AcOH/THF (v/v, 1/1). The resulting mixture was warmed
up and partitioned between EtOAc and saturated NaHCO3. The organic
layer was washed with H2O and dried over Na2SO4. After
concentration, the residue was purified by silica gel column
chromatography (hexanes/ethyl acetate, v/v, 2/1 to 1/1) to afford
compound 5 (330 mg) as a yellow solid. LC-MS (ESI): m/z 364 (M+1)+.

[0648] Step b. The resulting mixture of ester 3 and acid 3' was dissolved
in methanol (60 mL) and treated with aqueous lithium hydroxide (10 g in
20 mL of water, 240 mmol). The reaction mixture was refluxed for 4 h.
Methanol was evaporated under reduced pressure and the resulting aqueous
solution was washed with ethyl acetate (20 mL). The aqueous solution was
adjusted to pH 2 by the addition of 1 N HCl (aq) and extracted with ethyl
acetate (2×100 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo to give 4 (5.3 g, 92% yield)
as a yellow solid.

[0649] Step c. A nitrating mixture [1.17 mL, prepared from 67% HNO3
(3.52 mmol) and H2SO4] was added dropwise to a cooled mixture
of acid 4 (1.01 g, 3.52 mmol) in glacial acetic acid (8 mL) and acetic
anhydride (4 mL). The mixture was stirred at rt for 12 h and poured into
iced H2O. The precipitate was filtered off, washed with H2O to
neutral, and dried in vacuo to give 5 (0.72 g, 70% yield) as a yellow
solid.

[0650] Step d. A solution of 5 (2.7 g, 9.8 mmol) and 4 N HCl in dioxane
(20 mL) in methanol (30 mL) was stirred at rt overnight. The solvent was
evaporated, and the resulting residue was dissolved in ethyl acetate (50
mL) and washed with saturated NaHCO3 and brine. The organic phase
was concentrated and the resulting crude product was purified by silica
gel column chromatography (ethyl acetate/hexane=15/85 (v/v)) to give 6
(1.64 g, 60% yield) as a yellow solid.

[0655] Step i. A solution of acid obtained (0.57 g, 1.2 mmol) and oxalyl
chloride (1.05 mL, 12 mmol) in dichloromethane (5 mL) was stirred at rt
overnight. After concentrated under reduced pressure, the remaining
residue was dissolved in ether (10 mL) followed by addition of
diazomethane (20 mL, 0.33 N in ether, 6.8 mmol) at 0° C. The
reaction mixture was stirred at 0° C. for 30 min. The reaction
solution was concentrated and purified by silica gel column
chromatography (ethyl acetate/hexane=75/25 (v/v)) to give an isomeric
mixture (as a result of methylation on one of the benzimidazole
nitrogens) of diazoketones 11 and 11' (0.2 g, 35% yield).

[0659] Step m. A mixture of compounds 14 and 14' (83.3 mg, 0.13 mmol),
Pd/C (53.4 mg, 5% on carbon, 0.025 mmol) and one drop concentrated HCl in
ethanol (3 mL) under an atmosphere of hydrogen (15 psi) was stirred at rt
for 6 h. The reaction solution was then concentrated in vacuo to give
compounds 15 and 15' (75 mg, 90% yield). To a solution of the amines
obtained above (75 mg, 0.14 mmol) in THF (4 mL) was added 4N HCl in
dioxane (1 mL) at rt. The reaction mixture was stirred at rt for 2 h. The
solvent was evaporated and the residue was dried in vacuo to give
compounds 16 and 16' (50 mg, 83% yield) as a yellow solid.

[0661] Step a. Referring to Scheme 6-1, to a solution of N-Cbz-L-Pro-OH
(7.52 g, 30.0 mmol) and DIPEA (5.50 g, 54.0 mmol) in THF (200 mL) was
added HATU (11.5 g, 30.0 mmol) at rt. After stirring for 10 min,
4-bromobenzene-1,2-diamine (1) (5.10 g, 27.0 mmol) was added and the
reaction mixture was stirred at rt for 2 h. The mixture was concentrated
and the residue was diluted with EtOAc (250 mL) and water (50 mL). The
organic phase was washed with brine and dried with anhydrous
Na2SO4. The solvent was removed and the residue was dried in
vacuo to give crude compounds 2 and 2' (10.0 g), which were used for the
next step without further purification. LC-MS (ESI) m/z 418.1
(M+H)+.

[0662] Step b. A mixture of compounds 2 and 2' (10.0 g) in AcOH (100 mL)
was stirred at 40° C. for 12 h. The reaction mixture was then
neutralized by carefully adding saturated aqueous Na2CO3 to
adjust the pH value to 8. Subsequently, the reaction mixture was
extracted with EtOAc (150 mL×3). The extracts were combined, washed
with brine, and dried with anhydrous Na2SO4. The solvent was
removed and the residue was purified by silica gel column chromatography
(Petroleum ether/EtOAc=4/1 (v/v)) to give compound 3 (5.6 g, 70%) as a
yellow solid. LC-MS (ESI) m/z 400.1 (M+H)+.

[0663] Step c. To a mixture of compound 3 (5.05 g, 12.5 mmol),
bis(pinacolato)diboron (7.10 g, 26.3 mmol), and KOAc (3.20 g, 32.5 mmol)
in 1,4-dioxane (100 mL) was added Pd(dppf)Cl2 (400 mg, 0.5 mmol) at
rt under an atmosphere of N2. After stirring at 80° C. for 3
h under an atmosphere of N2, the reaction mixture was filtered
through CELITE®545 and the filtered cake was washed with EtOAc (100
mL×3). The filtrate was washed with brine and dried with anhydrous
Na2SO4. The solvent was removed and the residue was purified by
silica gel column chromatography (Petroleum ether/EtOAc=2/1 (v/v)) to
give compound 4 (3.0 g, 53%) as a gray solid: LC-MS (ESI) m/z 448.2
(M+H)+.

[0664] Step d. To a mixture of compound 4 (1.04 g, 2.20 mmol),
1,4-diiodobenzene (360 mg, 1.1 mmol), and NaHCO3 (650 mg, 7.7 mmol)
in 1,2-dimethoxyethane (36 mL) and water (12 mL) was added
Pd(dppf)Cl2 (80.0 mg, 0.10 mmol) at rt under an atmosphere of
N2. After stirring at 80° C. overnight under an atmosphere of
N2, the reaction mixture was concentrated and the residue was
diluted with EtOAc (100 mL) and water (25 mL). The organic phase was
washed with brine and dried with anhydrous Na2SO4. The solvent
was removed and the residue was purified by silica gel column
chromatography (DCM/MeOH=50/1 (v/v)) to give compound 5 (350 mg, 44%) as
a yellow solid. LC-MS (ESI) m/z 717.3 (M+H)+.

[0665] Step e. To a solution of compound 5 (200 mg, 0.28 mmol) in
CHCl3 (5 mL) was added TMSI (168 mg, 0.84 mmol) at rt. After
stirring at rt overnight, the reaction was quenched by adding MeOH (3.0
mL), followed by 4N HCl in dioxane (2.0 mL). The resulting mixture was
stirred at rt for 30 min and concentrated. The residue was washed with
DCM (10 mL) and dried in vacuo to give crude compound 6 (220 mg), which
was used for the next step without further purification. LC-MS (ESI) m/z
449.2 (M+H)+.

[0667] Step a. Referring to Scheme 6-2, to a solution of veratrol (8)
(40.0 g, 0.29 mol) in anhydrous THF (100 mL) and TMEDA (40 mL) was added
n-BuLi (2.5 M in hexanes, 128 mL, 0.32 mol) dropwise at rt under an
atmosphere of N2. After stirring at rt for 28 h under an atmosphere
of N2, the reaction mixture was cooled to -78° C., followed
by adding TMSCl (45 mL). The reaction mixture was stirred at rt for 5 h
and then added water (20 mL). The reaction mixture was concentrated and
the residue was extracted with hexane (100 mL×3). The extracts were
combined, washed with brine, and dried with anhydrous Na2SO4.
The solvent was removed and the residue was purified by silica gel column
chromatography to give compound 9 (42 g, 69%) as a colorless oil. LC-MS:
(ESI) m/z 211.1 (M+H)+.

[0668] Step b. To a solution of compound 9 (40 g, 0.20 mol) in anhydrous
TMEDA (40 mL) was added n-BuLi in hexanes (2.5 M, 120 mL, 0.24 mol)
dropwise at 0° C. under an atmosphere of N2. After stirring
at rt for 25 h, the reaction mixture was cooled to -78° C.,
followed by adding TMSCl (40 mL). The reaction mixture was stirred at rt
for 5 h and then added water (50 mL). The mixture was concentrated and
the residue was extracted with hexanes (100 mL×3). The extracts
were combined, washed with brine, and dried with anhydrous
Na2SO4. The solvent was removed and the residue was purified by
silica gel column chromatography to give compound 10 (52 g, 85%) as
colorless oil. LC-MS: (ESI) m/z 283.1 (M+H)+.

[0673] Step g. A mixture of compound 14 (150 mg, 0.21 mmol) in dioxane (2
mL) was added 4N HCl in dioxane (2 mL) at rt. After stirring at rt for 2
h, the reaction mixture was concentrated and the residue was dried in
vacuo to give an HCl salt, which was used for the next step without
further purification. LC-MS: (ESI) m/z 597.3 (M+H)+.

[0679] Step d. To a solution of (2S)-tert-butyl
2-(4-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-
phenyl)cyclohex-3-enylcarbamoyl)pyrrolidine-1-carboxylate (50 mg, 0.082
mmol) in DCM (15 mL), was added TFA (1 mL) at rt. After 1.5 h stirring,
the reaction was concentrated to give a TFA salt (5) (75 mg), which was
dissolved in anhydrous THF (5 mL). N-Boc-D-Phg-OH (51 mg, 0.21 mmol),
DMTMM (57 mg, 0.21 mmol) and Et3N (57 μL, 0.41 mmol) were added
at rt. After three days of stirring, the reaction was quenched with brine
and extracted with ethyl acetate. The combined organic phases were washed
with brine and H2O and dried over Na2SO4. After removal of
the solvent, the crude product was purified by prep-TLC (DCM/MeOH=10/1
(v/v)) to afford compound 6 (40 mg, 56% yield).

[0683] Biological activity of the compounds of the invention was
determined using an HCV replicon assay. The 1b_Huh-Luc/Neo-ET cell line
persistently expressing a bicistronic genotype 1b replicon in Huh 7 cells
was obtained from ReBLikon GMBH. This cell line was used to test
compound inhibition using luciferase enzyme activity readout as a
measurement of compound inhibition of replicon levels.

[0684] On Day 1 (the day after plating), each compound is added in
triplicate to the cells. Plates incubated for 72 h prior to running the
luciferase assay. Enzyme activity was measured using a Bright-Glo Kit
(cat. number E2620) manufactured by Promega Corporation. The following
equation was used to generate a percent control value for each compound.

% Control=(Average Compound Value/Average Control)*100

[0685] The EC50 value was determined using GraphPad Prism and the
following equation:

Y=Bottom+(Top-Bottom)/(1+10 ((Log IC50-X)*HillSlope))

[0686] EC50 values of compounds are repeated several times in the
replicon assay.

[0687] Example compounds of the disclosed invention are illustrated in
Tables 1-9 attached as appendices. The tables show inhibitory activity of
many of the example compounds with respect to HCV 1b. The biological
activity is indicated as being *, **, ***, or ****, which corresponds to
EC50 ranges of >1000 nM, 999 nM to 10 nM, 9.9 nM to 1 nM, or
<1 nM respectively. The tables further provide mass spectrometry
results for the synthesized example compounds.

[0688] Pharmaceutical Compositions

[0689] The sixteenth aspect of the invention provides a pharmaceutical
composition comprising the compounds of the invention. In a first
embodiment, the pharmaceutical composition further comprises one or more
pharmaceutically acceptable excipients or vehicles, and optionally other
therapeutic and/or prophylactic ingredients. Such excipients are known to
those of skill in the art. The compounds of the present invention
include, without limitation, basic compounds such as free bases. A
thorough discussion of pharmaceutically acceptable excipients and salts
is available in Remington's Pharmaceutical Sciences, 18th Edition
(Easton, Pa.: Mack Publishing Company, 1990).

[0690] Depending on the intended mode of administration, the
pharmaceutical compositions may be in the form of solid, semi-solid or
liquid dosage forms, such as, for example, tablets, suppositories, pills,
capsules, powders, liquids, suspensions, creams, ointments, lotions or
the like, preferably in unit dosage form suitable for single
administration of a precise dosage. The compositions will include an
effective amount of the selected drug in combination with a
pharmaceutically acceptable carrier and, in addition, may include other
pharmaceutical agents, adjuvants, diluents, buffers, etc.

[0691] The invention includes a pharmaceutical composition comprising a
compound of the present invention including isomers, racemic or
non-racemic mixtures of isomers, or pharmaceutically acceptable salts or
solvates thereof together with one or more pharmaceutically acceptable
carriers and optionally other therapeutic and/or prophylactic
ingredients.

[0693] For oral administration, the composition will generally take the
form of a tablet, capsule, a softgel capsule nonaqueous solution,
suspension or syrup. Tablets and capsules are preferred oral
administration forms. Tablets and capsules for oral use will generally
include one or more commonly used carriers such as lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. When liquid suspensions are used, the active agent may
be combined with emulsifying and suspending agents. If desired,
flavoring, coloring and/or sweetening agents may be added as well. Other
optional components for incorporation into an oral formulation herein
include, but are not limited to, preservatives, suspending agents,
thickening agents and the like.

[0694] The seventeenth aspect of the invention provides the use of the
compounds of the invention in the manufacture of a medicament.

[0695] In a first embodiment of the seventeenth aspect, the medicament is
for the treatment of hepatitis C.

[0696] The eighteenth aspect of the invention provides a method of
treating hepatitis C comprising administering to a subject in need
thereof, a therapeutically effective amount of a compound of the
invention, optionally in a pharmaceutical composition. A pharmaceutically
or therapeutically effective amount of the composition will be delivered
to the subject. The precise effective amount will vary from subject to
subject and will depend upon the species, age, the subject's size and
health, the nature and extent of the condition being treated,
recommendations of the treating physician, and the therapeutics or
combination of therapeutics selected for administration. Thus, the
effective amount for a given situation can be determined by routine
experimentation. The subject may be administered as many doses as is
required to reduce and/or alleviate the signs, symptoms or causes of the
disorder in question, or bring about any other desired alteration of a
biological system. One of ordinary skill in the art of treating such
diseases will be able, without undue experimentation and in reliance upon
personal knowledge and the disclosure of this application, to ascertain a
therapeutically effective amount of the compounds of this invention for a
given disease.

[0697] Combination Therapy

[0698] The compounds of the present invention and their isomeric forms and
pharmaceutically acceptable salts thereof are useful in treating and
preventing HCV infection alone or when used in combination with other
compounds targeting viral or cellular elements or functions involved in
the HCV lifecycle. Classes of compounds useful in the invention may
include, without limitation, all classes of HCV antivirals. For
combination therapies, mechanistic classes of agents that may be useful
when combined with the compounds of the present invention include, for
example, nucleoside and non-nucleoside inhibitors of the HCV polymerase,
protease inhibitors, helicase inhibitors, NS4B inhibitors and medicinal
agents that functionally inhibit the internal ribosomal entry site (IRES)
and other medicaments that inhibit HCV cell attachment or virus entry,
HCV RNA translation, HCV RNA transcription, replication or HCV
maturation, assembly or virus release. Specific compounds in these
classes and useful in the invention include, but are not limited to,
macrocyclic, heterocyclic and linear HCV protease inhibitors such as
telaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-900518),
ITMN-191 (R-7227), TMC-435350 (a.k.a. TMC-435), MK-7009, BI-201335,
BI-2061 (ciluprevir), BMS-650032, ACH-1625, ACH-1095 (HCV NS4A protease
co-factor inhibitor), VX-500, VX-813, PHX-1766, PHX2054, IDX-136,
IDX-316, ABT-450 EP-013420 (and congeners) and VBY-376; the Nucleosidic
HCV polymerase (replicase) inhibitors useful in the invention include,
but are not limited to, R7128, PSI-7851, IDX-184, IDX-102, R1479,
UNX-08189, PSI-6130, PSI-938 and PSI-879 and various other nucleoside and
nucleotide analogs and HCV inhibitors including (but not limited to)
those derived as 2'-C-methyl modified nucleos(t)ides, 4'-aza modified
nucleos(t)ides, and 7'-deaza modified nucleos(t)ides. Non-nuclosidic HCV
polymerase (replicase) inhibitors useful in the invention, include, but
are not limited to, HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598,
MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093,
JKT-109, GL-59728 and GL-60667.

[0699] In addition, NS5A inhibitors of the present invention may be used
in combination with cyclophyllin and immunophyllin antagonists (eg,
without limitation, DEBIO compounds, NM-811 as well as cyclosporine and
its derivatives), kinase inhibitors, of heat shock proteins (e.g., HSP90
and HSP70), other immunomodulatory agents that may include, without
limitation, interferons (-alpha, -beta, -omega, -gamma, -lambda or
synthetic) such as Intron A®, Roferon-A®, Canferon-A300®,
Advaferon®, Infergen®, Humoferon®, Sumiferon MP®,
Alfaferone®, IFN-β®, Feron® and the like; polyethylene
glycol derivatized (pegylated) interferon compounds, such as PEG
interferon-α-2a (Pegasys®), PEG interferon-α-2b
(PEGIntron®), pegylated IFN-α-con1 and the like; long acting
formulations and derivatizations of interferon compounds such as the
albumin-fused interferon, Albuferon®, Locteron® and the like;
interferons with various types of controlled delivery systems (e.g.
ITCA-638, omega-interferon delivered by the DUROS® subcutaneous
delivery system); compounds that stimulate the synthesis of interferon in
cells, such as resiquimod and the like; interleukins; compounds that
enhance the development of type 1 helper T cell response, such as SCV-07
and the like; TOLL-like receptor agonists such as CpG-10101 (actilon),
isotorabine, ANA773 and the like; thymosin α-1; ANA-245 and
ANA-246; histamine dihydrochloride; propagermanium; tetrachlorodecaoxide;
ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and
the like and prophylactic and therapeutic vaccines such as InnoVac C, HCV
E1E2/MF59 and the like. In addition, any of the above-described methods
involving administering an NS5A inhibitor, a Type I interferon receptor
agonist (e.g., an IFN-α) and a Type II interferon receptor agonist
(e.g., an IFN-γ) can be augmented by administration of an effective
amount of a TNF-α antagonist. Exemplary, non-limiting TNF-α
antagonists that are suitable for use in such combination therapies
include ENBREL®, REMICADE® and HUMIRA®.

[0700] In addition, NS5A inhibitors of the present invention may be used
in combination with antiprotozoans and other antivirals thought to be
effective in the treatment of HCV infection, such as, without limitation,
the prodrug nitazoxanide. Nitazoxanide can be used as an agent in
combination the compounds disclosed in this invention as well as in
combination with other agents useful in treating HCV infection such as
peginterferon alfa-2a and ribavarin (see, for example, Rossignol, J F and
Keeffe, E B, Future Microbiol. 3:539-545, 2008).

[0703] Combination therapy can be sequential, that is treatment with one
agent first and then a second agent (for example, where each treatment
comprises a different compound of the invention or where one treatment
comprises a compound of the invention and the other comprises one or more
biologically active agents) or it can be treatment with both agents at
the same time (concurrently). Sequential therapy can include a reasonable
time after the completion of the first therapy before beginning the
second therapy. Treatment with both agents at the same time can be in the
same daily dose or in separate doses. Combination therapy need not be
limited to two agents and may include three or more agents. The dosages
for both concurrent and sequential combination therapy will depend on
absorption, distribution, metabolism and excretion rates of the
components of the combination therapy as well as other factors known to
one of skill in the art. Dosage values will also vary with the severity
of the condition to be alleviated. It is to be further understood that
for any particular subject, specific dosage regimens and schedules may be
adjusted over time according to the individual's need and the
professional judgment of the person administering or supervising the
administration of the combination therapy.

[0704] All publications and patent applications cited in this
specification are herein incorporated by reference as if each individual
publication or patent application were specifically and individually
indicated to be incorporated by reference.

[0705] Although the foregoing invention has been described in some detail
by way of illustration and example for purposes of clarity of
understanding, it will be readily apparent to one of ordinary skill in
the art in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the spirit
or scope of the invention as defined in the appended claims.